%0 Journal Article
%~ PubMed
%A Williamson, Sarah L
%A Giudici, Laura
%A Kilstrup-Nielsen, Charlotte
%A Gold, Wendy
%A Pelka, Gregory J
%A Tam, Patrick P L
%A Grimm, Andrew
%A Prodi, Dionigio
%A Landsberger, Nicoletta
%A Christodoulou, John
%T A novel transcript of cyclin-dependent kinase-like 5 (CDKL5) has an alternative C-terminus and is the predominant transcript in brain.
%B Human Genetics
%D 2012
%C Germany
%I Springer
%V 131
%N 2
%P 187-200
%@ 0340-6717
%X The X-linked cyclin-dependent kinase-like 5 (CDKL5) gene is an important molecular determinant of early-onset intractable seizures with infantile spasms and Rett syndrome-like phenotype. The gene encodes a kinase that may influence components of molecular pathways associated with MeCP2. In humans there are two previously reported splice variants that differ in the 5'' untranslated exons and produce the same 115??kDa protein. Furthermore, very recently, a novel transcript including a novel exon (16b) has been described. By aligning both the human and mouse CDKL5 proteins to the orthologs of other species, we identified a theoretical 107??kDa isoform with an alternative C-terminus that terminates in intron 18. In human brain and all other tissues investigated except the testis, this novel isoform is the major CDKL5 transcript. The detailed characterisation of this novel isoform of CDKL5 reveals functional and subcellular localisation attributes that overlap greatly, but not completely, with that of the previously studied human CDKL5 protein. Considering its predominant expression in the human and mouse brain, we believe that this novel isoform is likely to be of primary pathogenic importance in human diseases associated with CDKL5 deficiency, and suggest that screening of the related intronic sequence should be included in the molecular genetic analyses of patients with a suggestive clinical phenotype.
%Z FOR Codes: 60405 60407


%0 Journal Article
%~ PubMed
%A Arkell, Ruth M
%A Tam, Patrick P L
%T Initiating head development in mouse embryos: integrating signalling and transcriptional activity.
%B Open Biology
%D 2012
%C United Kingdom
%I The Royal Society Publishing
%V 2
%N 3
%P 120030
%@ 2046-2441
%X The generation of an embryonic body plan is the outcome of inductive interactions between the progenitor tissues that underpin their specification, regionalization and morphogenesis. The intercellular signalling activity driving these processes is deployed in a time- and site-specific manner, and the signal strength must be precisely controlled. Receptor and ligand functions are modulated by secreted antagonists to impose a dynamic pattern of globally controlled and locally graded signals onto the tissues of early post-implantation mouse embryo. In response to the WNT, Nodal and Bone Morphogenetic Protein (BMP) signalling cascades, the embryo acquires its body plan, which manifests as differences in the developmental fate of cells located at different positions in the anterior-posterior body axis. The initial formation of the anterior (head) structures in the mouse embryo is critically dependent on the morphogenetic activity emanating from two signalling centres that are juxtaposed with the progenitor tissues of the head. A common property of these centres is that they are the source of antagonistic factors and the hub of transcriptional activities that negatively modulate the function of WNT, Nodal and BMP signalling cascades. These events generate the scaffold of the embryonic head by the early-somite stage of development. Beyond this, additional tissue interactions continue to support the growth, regionalization, differentiation and morphogenesis required for the elaboration of the structure recognizable as the embryonic head.
%Z FOR Codes: 60403 699


%0 Journal Article
%~ PubMed
%A Stephenson, Robert O
%A Rossant, Janet
%A Tam, Patrick P L
%T Intercellular interactions, position, and polarity in establishing blastocyst cell lineages and embryonic axes.
%B Cold Spring Harbor Perspectives in Biology
%D 2012
%C United States
%I Cold Spring Harbor Laboratory Press
%V 4
%N 11
%P a008235
%@ 1943-0264
%X 
%Z FOR Codes: 69999


%0 Journal Article
%~ PubMed
%A Fossat, Nicolas
%A Jones, Vanessa
%A Garcia-Garcia, Maria J
%A Tam, Patrick P L
%T Modulation of WNT signaling activity is key to the formation of the embryonic head.
%B Cell Cycle
%D 2012
%C United States
%I Landes Bioscience
%V 11
%N 1
%P 26-32
%@ 1551-4005
%X The formation of the embryonic head begins with the assembly of the progenitor tissues of the brain, the head and face primordia and the foregut that are derived from the primary germ layers during gastrulation. Specification of the anterior-posterior polarity of major body parts and the morphogenesis of the head and brain specifically is driven by inductive signals including those mediated by BMP, Nodal, FGF and WNT. A critical role of ?-catenin dependent WNT signalling activity for head morphogenesis has been revealed through the analysis of the phenotypic impact of loss of function mutation of an antagonist: DKK1, a transcriptional repressor: GSC; and the outcome of interaction of Dkk1 with genes coding three components of the canonical signalling pathway: the ligand WNT3, the co-receptor LRP6 and the transcriptional co-factor, ?-catenin. The findings highlight the requirement of a stringent control of the timing, domain and level of canonical WNT signalling activity for the formation of the embryonic head.
%Z FOR Codes: 604 602


%0 Journal Article
%~ PubMed
%A Loebel, David A F
%A Hor, Angelyn C C
%A Bildsoe, Heidi
%A Jones, Vanessa
%A Chen, You-Tzung
%A Behringer, Richard R
%A Tam, Patrick P L
%T Regionalized Twist1 activity in the forelimb bud drives the morphogenesis of the proximal and preaxial skeleton.
%B Developmental biology
%D 2012
%C United States
%I Academic Press
%V 362
%N 2
%P 132-40
%@ 1095-564X
%X Development of the mouse forelimb bud depends on normal Twist1 activity. Global loss of Twist1 function before limb bud formation stops limb development and loss of Twist1 throughout the mesenchyme after limb bud initiation leads to polydactyly, the ulnarization or loss of the radius and malformations and reductions of the shoulder girdle. Here we show that conditional deletion of Twist1 by Mesp1-Cre in the mesoderm that migrates into the anterior-proximal part of the forelimb bud results in the development of supernumerary digits and carpals, the acquisition of ulna-like characteristics by the radius and malformations of the humerus and scapula. The mirror-like duplications and posteriorization of pre-axial tissues are preceded by disruptions to anterior-posterior Shh, Bmp and Fgf signaling gradients and dysregulation of transcription factors that regulate anterior-posterior limb patterning.
%Z FOR Codes: 60403 60803


%0 Journal Article
%~ PubMed
%A Loebel, David A F
%A Tam, Patrick P L
%T Rho GTPases in endoderm development and differentiation.
%B Small GTPases
%D 2012
%C United States
%I Landes Bioscience
%V 3
%N 1
%P 40-44
%@ 2154-1256
%X The embryonic foregut of the mouse embryo is lined by a layer of endoderm cells whose architecture changes during development. The transition from a squamous to columnar epithelial morphology is accompanied by the upregulation of an atypical Rho GTPase, Rhou. Subsequently, multi-layering of the epithelium at the site of organ bud formation is associated with the downregulation of Rhou. Rho-related small GTPases are known to play multiple roles in establishing and maintaining epithelial polarity, cytoskeletal organization, morphogenesis and differentiation of epithelial tissues, but their role in the early development of the endoderm in mammals is largely unexplored. Our recent study has shown that Rhou is required for maintaining F-actin polarization, epithelial morphogenesis and differentiation of the endoderm. Rhou expression responds to canonical WNT signaling and its activity influences the cytoskeletal organization and differentiation of endodermal cells, possibly via activation of JNK-mediated pathways. In this context, Rhou provides a possible link between ??-catenin dependent WNT signaling and cellular processes normally associated with WNT/PCP pathways.
%Z FOR Codes: 601 699


%0 Journal Article
%~ PubMed
%A Tam, Patrick
%T Endoderm formation: not so black and white anymore.
%B Developmental Cell
%D 2011
%C United States
%I Cell Press
%V 21
%N 4
%P e2
%@ 1878-1551
%X This study illustrates how the combination of innovative genetic mouse models, embryological experimentation, and live-imaging techniques can resolve longstanding questions in endoderm formation during early mouse development. Kwon et??al. showed that cells recruited from the epiblast during germ layer formation in the mouse embryo are not always incorporated into the endoderm in the immediate vicinity of the primitive streak. Beyond demonstrating that the mouse is just like a chick in its strategy for definitive (gut) endoderm recruitment, this finding resolved the enigmatic observation that some epiblast-derived cells in the endoderm are localized further from the site of ingression than anticipated based on "conventional" wisdom. Through tracking of the distribution of the visceral endoderm pre-existing prior to gastrulation, descendants of the visceral endoderm were found, surprisingly, to colonize the embryonic gut, thus dispelling the myth that visceral endoderm differs from the so-called "definitive" endoderm in its inability to contribute to the embryonic gut and that it is replaced wholesale by the nascent population recruited during gastrulation. This paper thus delineated a paradigm of mouse endoderm formation and presented us with the challenge of determining the ultimate fates of these visceral endoderm cells in the fetal and adult gut. This PaperPick refers to "The Endoderm of the Mouse Embryo Arises by Dynamic Widespread Intercalation of Embryonic and Extraembryonic Lineages," by G.S. Kwon, M. Viotti, and A.K. Hadjantonakis, published in October 2008. VIDEO ABSTRACT:
%Z FOR Codes: 69999 60602


%0 Journal Article
%~ PubMed
%A Combes, A N
%A Bowles, J
%A Feng, C-W
%A Chiu, H S
%A Khoo, P-L
%A Jackson, A
%A Little, M H
%A Tam, P P L
%A Koopman, P
%T Expression and functional analysis of Dkk1 during early gonadal development.
%B Sexual Development
%D 2011
%C Switzerland
%I S. Karger AG
%V 5
%N 3
%P 124-130
%@ 1661-5433
%X WNT signalling plays a central role in mammalian sex determination by promoting ovarian development and repressing aspects of testis development in the early gonad. Dickkopf homolog 1 (DKK1) is a WNT signalling antagonist that plays critical roles in multiple developmental systems by modulating WNT activity. Here, we examined the role of DKK1 in mouse sex determination and early gonadal development. Dkk1 mRNA was upregulated sex-specifically during testis differentiation, suggesting that DKK1 could repress WNT signalling in the developing testis. However, we observed overtly normal testis development in Dkk1-null XY gonads, and found no significant upregulation of Axin2 or Sp5 that would indicate increased canonical WNT signalling. Nor did we find significant differences in expression of key markers of testis and ovarian development. We propose that DKK1 may play a protective role that is not unmasked by loss-of-function in the absence of other stressors.
%Z FOR Codes: 111404


%0 Journal Article
%~ PubMed
%A Tanaka, Satomi S
%A Kojima, Yoji
%A Yamaguchi, Yasuka L
%A Nishinakamura, Ryuichi
%A Tam, Patrick P L
%T Impact of WNT signaling on tissue lineage differentiation in the early mouse embryo.
%B Development, growth & differentiation
%D 2011
%C Australia
%I Wiley-Blackwell Publishing Asia
%V 53
%N 7
%P 843-56
%@ 1440-169X
%X WNT signaling activity is involved in the regulation of many cellular functions, including proliferation, migration, cell fate specification, maintenance of pluripotency and induction of tumorigenicity. Here we summarize recent progress towards understanding the regulation of canonical WNT/??-catenin signaling activity through feedback regulatory loops involving the ligands, agonists and antagonists, the availability of intracellular pools of active ??-catenin and the cross-regulation of the WNT activity by ??-catenin independent pathway. We also review recent findings on the role of WNT/??-catenin signaling in tissue lineage differentiation during embryogenesis and the maintenance and self renewal of embryo-derived stem cells in vitro.
%Z FOR Codes: 69999 60403 60111


%0 Book Section
%A Fossat, Nicolas
%A Loebel, David
%A Jones, Vanessa
%A Khoo, Poh-Lynn
%A Bildsoe, Heidi
%A Tam, Patrick
%T Marking Cells for Imaging Analysis of
Morphogenetic Behavior and Cell Fates
in Mouse Embryos
%B Imaging in Developmental Biology: A Laboratory Manual
%D 2011
%C United States
%I Cold Spring Harbor Laboratory Press
%V 
%N 
%P 311-329
%@ 9780879699406
%E Sharpe, James
%E Wong, Rachel
%X 
%Z FOR Codes: 110320 60103


%0 Journal Article
%~ PubMed
%A Loebel, David A F
%A Studdert, Joshua B
%A Power, Melinda
%A Radziewic, Tania
%A Jones, Vanessa
%A Coultas, Leigh
%A Jackson, Yvette
%A Rao, Renuka S
%A Steiner, Kirsten
%A Fossat, Nicolas
%A Robb, Lorraine
%A Tam, Patrick P L
%T Rhou maintains the epithelial architecture and facilitates differentiation of the foregut endoderm.
%B Development
%D 2011
%C United Kingdom
%I The Company of Biologists Ltd.
%V 138
%N 20
%P 4511-4522
%@ 1477-9129
%X Rhou encodes a Cdc42-related atypical Rho GTPase that influences actin organization in cultured cells. In mouse embryos at early-somite to early-organogenesis stages, Rhou is expressed in the columnar endoderm epithelium lining the lateral and ventral wall of the anterior intestinal portal. During foregut development, Rhou is downregulated in regions where the epithelium acquires a multilayered morphology heralding the budding of organ primordia. In embryos generated from Rhou knockdown embryonic stem (ES) cells, the embryonic foregut displays an abnormally flattened shape. The epithelial architecture of the endoderm is disrupted, the cells are depleted of microvilli and the phalloidin-stained F-actin content of their sub-apical cortical domain is reduced. Rhou-deficient cells in ES cell-derived embryos and embryoid bodies are less efficient in endoderm differentiation. Impaired endoderm differentiation of Rhou-deficient ES cells is accompanied by reduced expression of c-Jun/AP-1 target genes, consistent with a role for Rhou in regulating JNK activity. Downregulation of Rhou in individual endoderm cells results in a reduced ability of these cells to occupy the apical territory of the epithelium. Our findings highlight epithelial morphogenesis as a required intermediate step in the differentiation of endoderm progenitors. In vivo, Rhou activity maintains the epithelial architecture of the endoderm progenitors, and its downregulation accompanies the transition of the columnar epithelium in the embryonic foregut to a multilayered cell sheet during organ formation.
%Z FOR Codes: 60403 60803


%0 Journal Article
%~ PubMed
%A Pfister, Sabine
%A Jones, Vanessa J
%A Power, Melinda
%A Truisi, Germaine L
%A Khoo, Poh-Lynn
%A Steiner, Kirsten A
%A Kanai-Azuma, Masami
%A Kanai, Yoshiakira
%A Tam, Patrick P L
%A Loebel, David A F
%T Sox17-dependent gene expression and early heart and gut development in Sox17-deficient mouse embryos.
%B The International Journal of Developmental Biology
%D 2011
%C Spain
%I Universidad del Pais Vasco
%V 55
%N 1
%P 45-58
%@ 1696-3547
%X Sox17 is a transcription factor that is required for maintenance of the definitive endoderm in mouse embryos. By expression profiling of wild-type and mutant embryos and Sox17-overexpressing hepatoma cells, we identified genes with Sox17-dependent expression. Among the genes that were up-regulated in Sox17-null embryos and down-regulated by Sox17 expressing HepG2 cells is a set of genes that are expressed in the developing liver, suggesting that one function of Sox17 is the repression of liver gene expression, which is compatible with a role for Sox17 in maintaining the definitive endoderm in a progenitor state. Consistent with these findings, Sox17(-/-) cells display a diminished capacity to contribute to the definitive endoderm when transplanted into wild-type hosts. Analysis of gene ontology further revealed that many genes related to heart development were downregulated in Sox17-null embryos. This is associated with the defective development of the heart in the mutant embryos, which is accompanied by localised loss of Myocd-expressing cardiogenic progenitors and the malformation of the anterior intestinal portal.
%Z FOR Codes: 60403 60803 60405


%0 Journal Article
%~ PubMed
%A Fossat, Nicolas
%A Jones, Vanessa
%A Khoo, Poh-Lynn
%A Bogani, Debora
%A Hardy, Andrea
%A Steiner, Kirsten
%A Mukhopadhyay, Mahua
%A Westphal, Heiner
%A Nolan, Patrick M
%A Arkell, Ruth
%A Tam, Patrick P L
%T Stringent requirement of a proper level of canonical WNT signalling activity for head formation in mouse embryo.
%B Development
%D 2011
%C United Kingdom
%I The Company of Biologists Ltd.
%V 138
%N 4
%P 667-676
%@ 1477-9129
%X In mouse embryos, loss of Dickkopf-1 (DKK1) activity is associated with an ectopic activation of WNT signalling responses in the precursors of the craniofacial structures and leads to a complete truncation of the head at early organogenesis. Here, we show that ENU-induced mutations of genes coding for two WNT canonical pathway factors, the co-receptor LRP6 and the transcriptional co-activator ?-catenin, also elicit an ectopic signalling response and result in loss of the rostral tissues of the forebrain. Compound mutant embryos harbouring combinations of mutant alleles of Lrp6, Ctnnb1 and Dkk1 recapitulate the partial to complete head truncation phenotype of individual homozygous mutants. The demonstration of a synergistic interaction of Dkk1, Lrp6 and Ctnnb1 provides compelling evidence supporting the concepts that (1) stringent regulation of the level of canonical WNT signalling is necessary for head formation, (2) activity of the canonical pathway is sufficient to account for the phenotypic effects of mutations in three different components of the signal cascade and (3) rostral parts of the brain and the head are differentially more sensitive to canonical WNT signalling and their development is contingent on negative modulation of WNT signalling activity.
%Z FOR Codes: 69999 60803 60803


%0 Journal Article
%~ PubMed
%A Harikrishnan, K N
%A Bayles, Richard
%A Ciccotosto, Giuseppe D
%A Maxwell, Scott
%A Cappai, Roberto
%A Pelka, Gregory J
%A Tam, Patrick P L
%A Christodoulou, John
%A El-Osta, Assam
%T Alleviating transcriptional inhibition of the norepinephrine slc6a2 transporter gene in depolarized neurons.
%B The Journal of Neuroscience
%D 2010
%C United States
%I Society for Neuroscience
%V 30
%N 4
%P 1494-1501
%@ 1529-2401
%X Recent studies have brought to light additional experimental information, namely, that the MeCP2 protein complex is not only capable of associating with members of the ATPase-dependent bromodomain family, but also found on nonmethylated genomic sequences. These unexpected results are indicative of a multifunctional role for MeCP2, more importantly; our view of the molecular mechanisms that regulate gene activity may not be necessarily distinguishable. Depolarized mouse neuronal cortical cells were examined for increased Slc6a2 mRNA synthesis, changes in CpG methylation status using bisulfite sequencing, and binding of MeCP2 and Smarca2 on the Slc6a2 promoter sequence by chromatin immunopurification strategies. Increased Slc6a2 gene expression in response to membrane depolarization was strongly correlated with the dissociation of MeCP2 and Smarca2 complex on the unmethylated gene. We identified that gene expression in neuronal cortical cells involves increased histone hyperacetylation on the Slc6a2 promoter, which is commensurate with the recruitment of SP1 and RNA Polymerase II and is inversely correlated with H3K9 trimethylation. We hypothesize that the MeCP2 corepressor is capable of associating with multiple forms of SWI/SNF to remodel chromatin for important regulatory roles. The results of our experiments indicate that these proteins are asymmetrically bound to chromatin independent of DNA methylation and not inevitably diametrically opposed. These results now begin to offer a new perspective on the mechanism of Slc6a2 gene regulation.
%Z FOR Codes: 60199 110902


%0 Book Section
%A Rivera-Pérez, Jaime A.
%A Jones, Vanessa
%A Tam, Patrick
%T Culture of Whole Mouse Embryos at Early Postimplantation to Organogenesis Stages: Developmental Staging and Methods
%B Methods in Enzymology: Guide to Techniques in Mouse Development, Part A: Mice, Embryos, and Cells
%D 2010
%C United States
%I Elsevier Inc.
%V 
%N 
%P 185-203
%@ 9780123747754
%E Wassarman, Paul M.
%E Soriano, Philippe M.
%X 
%Z FOR Codes: 60107


%0 Journal Article
%~ PubMed
%A Pera, Martin F
%A Tam, Patrick P L
%T Extrinsic regulation of pluripotent stem cells.
%B Nature
%D 2010
%C United Kingdom
%I Nature Publishing Group
%V 465
%N 7299
%P 713-720
%@ 0028-0836
%X During early mammalian development, as the pluripotent cells that give rise to all of the tissues of the body proliferate and expand in number, they pass through transition states marked by a stepwise restriction in developmental potential and by changes in the expression of key regulatory genes. Recent findings show that cultured stem-cell lines derived from different stages of mouse development can mimic these transition states. They further reveal that there is a high degree of heterogeneity and plasticity in pluripotent populations in vitro and that these properties are modulated by extrinsic signalling. Understanding the extrinsic control of plasticity will guide efforts to use human pluripotent stem cells in research and therapy.
%Z FOR Codes: 699 60103 60403


%0 Journal Article
%~ PubMed
%A Tanaka, Satomi S
%A Yamaguchi, Yasuka L
%A Steiner, Kirsten A
%A Nakano, Toru
%A Nishinakamura, Ryuichi
%A Kwan, Kin Ming
%A Behringer, Richard R
%A Tam, Patrick P L
%T Loss of Lhx1 activity impacts on the localization of primordial germ cells in the mouse.
%B Developmental dynamics : an official publication of the American Association of Anatomists
%D 2010
%C United States
%I John Wiley & Sons, Inc.
%V 239
%N 11
%P 2851-9
%@ 1097-0177
%X Mouse embryos lacking Lhx1 (Lim1) activity display defective gastrulation and are deficient of primordial germ cells (PGCs) (Tsang et al. [2001] International Journal of Developmental Biology 45:549-555). To dissect the specific role of Lhx1 in germ cell development, we studied embryos with conditional inactivation of Lhx1 activity in epiblast derivatives, which, in contrast to completely null embryos, develop normally through gastrulation before manifesting a head truncation phenotype. Initially, PGCs are localized properly to the definitive endoderm of the posterior gut in the conditional mutant embryos, but they depart from the embryonic gut prematurely. The early exit of PGCs from the gut is accompanied by the failure to maintain a strong expression of Ifitm1 in the mesoderm enveloping the gut, which may mediate the repulsive activity that facilitates the retention of PGCs in the hindgut during early organogenesis. Lhx1 therefore may influence the localization of PGCs by modulating Ifitm1-mediated repulsive activity.
%Z FOR Codes: 69999 60403


%0 Journal Article
%~ PubMed
%A Leung, Alan W L
%A Wong, Sandra Y Y
%A Chan, Danny
%A Tam, Patrick P L
%A Cheah, Kathryn S E
%T Loss of procollagen IIA from the anterior mesendoderm disrupts the development of mouse embryonic forebrain.
%B Developmental Dynamics
%D 2010
%C United States
%I John Wiley & Sons, Inc.
%V 239
%N 9
%P 2319-2329
%@ 1097-0177
%X Morphogenesis of the mammalian forebrain is influenced by the patterning activity of signals emanating from the anterior mesendoderm. In this study, we show that procollagen IIA (IIA), an isoform of the cartilage extracellular matrix protein encoded by an alternatively spliced transcript of Col2a1, is expressed in the prechordal plate and the anterior definitive endoderm. In the absence of IIA activity, the null mutants displayed a partially penetrant phenotype of loss of head tissues, holoprosencephaly, and loss of mid-facial structures, which is associated with reduced sonic hedgehog (Shh) expression in the prechordal mesoderm. Genetic interaction studies reveal that IIA function in forebrain and face development does not involve bone morphogenetic protein receptor 1A (BMPR1A)- or NODAL-mediated signaling activity. Developmental Dynamics 239:2319-2329. © 2010 Wiley-Liss, Inc.
%Z FOR Codes: 69999 60403 60803


%0 Journal Article
%~ PubMed
%A Fath, Thomas
%A Agnes Chan, Yee-Ka
%A Vrhovski, Bernadette
%A Clarke, Hamish
%A Curthoys, Nikki
%A Hook, Jeff
%A Lemckert, Frances
%A Schevzov, Galina
%A Tam, Patrick
%A Watson, Catherine M
%A Khoo, Poh-Lynn
%A Gunning, Peter
%T New aspects of tropomyosin-regulated neuritogenesis revealed by the deletion of Tm5NM1 and 2.
%B European journal of cell biology
%D 2010
%C Germany
%I Urban und Fischer Verlag
%V 89
%N 7
%P 489-98
%@ 1618-1298
%X Previous studies have shown that the overexpression of tropomyosins leads to isoform-specific alterations in the morphology of subcellular compartments in neuronal cells. Here we have examined the role of the most abundant set of isoforms from the gamma-Tm gene by knocking out the alternatively spliced C-terminal exon 9d. Despite the widespread location of exon 9d-containing isoforms, mice were healthy and viable. Compensation by products containing the C-terminal exon 9c was seen in the adult brain. While neurons from these mice show a mild phenotype at one day in culture, neurons revealed a significant morphological alteration with an increase in the branching of dendrites and axons after four days in culture. Our data suggest that this effect is mediated via altered stability of actin filaments in the growth cones. We conclude that exon 9d-containing isoforms are not essential for survival of neuronal cells and that isoform choice from the gamma-Tm gene is flexible in the brain. Although functional redundancy does not exist between tropomyosin genes, these results suggest that significant redundancy exists between products from the same gene.
%Z FOR Codes: 699


%0 Journal Article
%~ PubMed
%A Weaving, Linda
%A Mihelec, Marija
%A Storen, Rebecca
%A Sosic, Drazen
%A Grigg, John R
%A Tam, Patrick P
%A Jamieson, Robyn V
%T Twist2: Role in Corneal Stromal Keratocyte Proliferation and Corneal Thickness.
%B Investigative ophthalmology & visual science
%D 2010
%C United States
%I Association for Research in Vision and Ophthalmology
%V 51
%N 11
%P 5561-70
%@ 0146-0404
%X Twist2 is a member of a family of bHLH transcription factors critical for normal mesenchymal proliferation and differentiation. In this study, the authors analyzed the role of Twist2 in the eye and cornea through examination of a Twist2 loss-of-function mouse mutant.
%Z FOR Codes: 60403 110311 111303


%0 Journal Article
%~ PubMed
%A Rossant, Janet
%A Tam, Patrick P L
%T Blastocyst lineage formation, early embryonic asymmetries and axis patterning in the mouse.
%B Development
%D 2009
%C United Kingdom
%I The Company of Biologists Ltd.
%V 136
%N 5
%P 701-713
%@ 0950-1991
%X The investigation into lineage allocation and early asymmetries in the pre- and peri-implantation mouse embryo is gaining momentum. As we review here, new insights have been gained into the cellular and molecular events that lead to the establishment of the three lineages of the blastocyst, to the determination of the origin and the fates of the visceral endoderm in the peri-implantation mouse embryo, and to the generation of cellular and molecular activities that accompany the emergence of asymmetries in the pre-gastrulation embryo. We also discuss the continuing debate that surrounds the relative impacts of early lineage bias versus the stochastic allocation of cells with respect to the events that pattern the blastocyst and initiate its later asymmetries.
%Z FOR Codes: 60803


%0 Journal Article
%~ PubMed
%A Mihelec, Marija
%A Abraham, Peter
%A Gibson, Kate
%A Krowka, Renata
%A Susman, Rachel
%A Storen, Rebecca
%A Chen, Yongjuan
%A Donald, Jenny
%A Tam, Patrick Pl
%A Grigg, John R
%A Flaherty, Maree
%A Gole, Glen A
%A Jamieson, Robyn V
%T Novel SOX2 partner-factor domain mutation in a four-generation family.
%B European journal of human genetics : EJHG
%D 2009
%C United Kingdom
%I Nature Publishing Group
%V 17
%N 11
%P 1417-22
%@ 1476-5438
%X Anophthalmia (no eye), microphthalmia (small eye) and associated ocular developmental anomalies cause significant visual handicap. In most cases the underlying genetic cause is unknown, but mutations in some genes, such as SOX2, cause ocular developmental defects, particularly anophthalmia, in a subset of patients. Here, we describe a four-generation family with a p.Asp123Gly mutation in the highly conserved partner-factor interaction region of the SOX2 protein, which is important for cell-specific actions of SOX2. The proband in this family has bilateral anophthalmia and several other family members have milder ocular phenotypes, including typical optic fissure coloboma. Expression studies indicate that Sox2 is expressed in the eye at the site of closure of the optic fissure during development. The SOX2 mutation in this family implicates the partner-factor interaction region of SOX2 in contributing to the specificity of SOX2 action in optic fissure closure. Our findings indicate that investigation of SOX2 in a broad range of eye anomaly patients aids in the determination of particular functions of SOX2 in development.
%Z FOR Codes: 104


%0 Journal Article
%~ PubMed
%A Bildsoe, Heidi
%A Loebel, David A F
%A Jones, Vanessa J
%A Chen, You-Tzung
%A Behringer, Richard R
%A Tam, Patrick P L
%T Requirement for Twist1 in frontonasal and skull vault development in the mouse embryo.
%B Developmental Biology
%D 2009
%C United States
%I Academic Press
%V 331
%N 2
%P 176-188
%@ 0012-1606
%X Using a Cre-mediated conditional deletion approach, we have dissected the function of Twist1 in the morphogenesis of the craniofacial skeleton. Loss of Twist1 in neural crest cells and their derivatives impairs skeletogenic differentiation and leads to the loss of bones of the snout, upper face and skull vault. While no anatomically recognizable maxilla is formed, a malformed mandible is present. Since Twist1 is expressed in the tissues of the maxillary eminence and the mandibular arch, this finding suggests that the requirement for Twist1 is not the same in all neural crest derivatives. The effect of the loss of Twist1 function is not restricted to neural crest-derived bones, since the predominantly mesoderm-derived parietal and interparietal bones are also affected, presumably as a consequence of lost interactions with neural crest-derived tissues. In contrast, the formation of other mesodermal skeletal derivatives such as the occipital bones and most of the chondrocranium are not affected by the loss of Twist1 in the neural crest cells.
%Z FOR Codes: 699


%0 Journal Article
%~ PubMed
%A Tam, Patrick P L
%A Loebel, David A F
%T Specifying mouse embryonic germ cells.
%B Cell
%D 2009
%C United States
%I Cell Press
%V 137
%N 3
%P 398-400
%@ 1097-4172
%X Male germ cells are induced to form from the epiblast of the mouse embryo by a combination of WNT and bone morphogenetic protein signals. Ohinata et al. (2009) now clarify the steps of mouse germ cell formation and use this genetic insight to direct the specification and differentiation of germline progenitor cells in vitro.
%Z FOR Codes: 699


%0 Journal Article
%~ PubMed
%A Grassinger, Jochen
%A Haylock, David N
%A Storan, Melonie J
%A Haines, Gemma O
%A Williams, Brenda
%A Whitty, Genevieve A
%A Vinson, Andrew R
%A Be, Cheang Ly
%A Li, Songhui
%A Sřrensen, Esben S
%A Tam, Patrick P L
%A Denhardt, David T
%A Sheppard, Dean
%A Choong, Peter F
%A Nilsson, Susan K
%T Thrombin-cleaved osteopontin regulates hemopoietic stem and progenitor cell functions through interactions with alpha9beta1 and alpha4beta1 integrins.
%B Blood
%D 2009
%C United States
%I American Society of Hematology
%V 114
%N 1
%P 49-59
%@ 0006-4971
%X Osteopontin (OPN), a multifunctional acidic glycoprotein, expressed by osteoblasts within the endosteal region of the bone marrow (BM) suppresses the proliferation of hemopoietic stem and progenitor cells and also regulates their lodgment within the BM after transplantation. Herein we demonstrate that OPN cleavage fragments are the most abundant forms of this protein within the BM. Studies aimed to determine how hemopoietic stem cells (HSCs) interact with OPN revealed for the first time that murine and human HSCs express alpha(9)beta(1) integrin. The N-terminal thrombin cleavage fragment of OPN through its binding to the alpha(9)beta(1) and alpha(4)beta(1) integrins plays a key role in the attraction, retention, regulation, and release of hemopoietic stem and progenitor cells to, in, and from their BM niche. Thrombin-cleaved OPN (trOPN) acts as a chemoattractant for stem and progenitor cells, mediating their migration in a manner that involves interaction with alpha(9)beta(1) and alpha(4)beta(1) integrins. In addition, in the absence of OPN, there is an increased number of white blood cells and, specifically, stem and progenitor cells in the peripheral circulation.
%Z FOR Codes: 60106


%0 Journal Article
%~ PubMed
%A Watson, Catherine M
%A Trainor, Paul A
%A Radziewic, Tania
%A Pelka, Gregory J
%A Zhou, Sheila X
%A Parameswaran, Maala
%A Quinlan, Gabriel A
%A Gordon, Monica
%A Sturm, Karin
%A Tam, Patrick P L
%T Application of lacZ Transgenic Mice to Cell Lineage Studies.
%B Methods in Molecular Biology
%D 2008
%C United States
%I Humana Press
%V 461
%N 
%P 149-164
%@ 1064-3745
%X 
%Z FOR Codes: 60103


%0 Journal Article
%~ PubMed
%A Furtado, Milena B
%A Solloway, Mark J
%A Jones, Vanessa J
%A Costa, Mauro W
%A Biben, Christine
%A Wolstein, Orit
%A Preis, Jost I
%A Sparrow, Duncan B
%A Saga, Yumiko
%A Dunwoodie, Sally L
%A Robertson, Elizabeth J
%A Tam, Patrick P L
%A Harvey, Richard P
%T BMP/SMAD1 signaling sets a threshold for the left/right pathway in lateral plate mesoderm and limits availability of SMAD4.
%B Genes & development
%D 2008
%C United States
%I Cold Spring Harbor Laboratory Press
%V 22
%N 21
%P 3037-3049
%@ 0890-9369
%X Bistability in developmental pathways refers to the generation of binary outputs from graded or noisy inputs. Signaling thresholds are critical for bistability. Specification of the left/right (LR) axis in vertebrate embryos involves bistable expression of transforming growth factor beta (TGFbeta) member NODAL in the left lateral plate mesoderm (LPM) controlled by feed-forward and feedback loops. Here we provide evidence that bone morphogenetic protein (BMP)/SMAD1 signaling sets a repressive threshold in the LPM essential for the integrity of LR signaling. Conditional deletion of Smad1 in the LPM led to precocious and bilateral pathway activation. NODAL expression from both the left and right sides of the node contributed to bilateral activation, indicating sensitivity of mutant LPM to noisy input from the LR system. In vitro, BMP signaling inhibited NODAL pathway activation and formation of its downstream SMAD2/4-FOXH1 transcriptional complex. Activity was restored by overexpression of SMAD4 and in embryos, elevated SMAD4 in the right LPM robustly activated LR gene expression, an effect reversed by superactivated BMP signaling. We conclude that BMP/SMAD1 signaling sets a bilateral, repressive threshold for NODAL-dependent Nodal activation in LPM, limiting availability of SMAD4. This repressive threshold is essential for bistable output of the LR system.
%Z FOR Codes: 110299 60402


%0 Journal Article
%~ PubMed
%A Gabriel, A Quinlan
%A Khoo, Poh-Lynn
%A Wong, Nicole
%A Paul, A Trainor
%A Patrick, P L Tam
%T Cell grafting and labeling in postimplantation mouse embryos.
%B Methods in Molecular Biology
%D 2008
%C United States
%I Springer
%V 461
%N 0
%P 47-70
%@ 1064-3745
%X 
%Z FOR Codes: 60103


%0 Journal Article
%~ PubMed
%A Mihelec, Marija
%A St Heaps, Luke
%A Flaherty, Maree
%A Billson, Frank
%A Rudduck, Christina
%A Tam, Patrick P L
%A Grigg, John R
%A Peters, Greg B
%A Jamieson, Robyn V
%T Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.
%B Twin Research and Human Genetics
%D 2008
%C Australia
%I Australian Academic Press
%V 11
%N 4
%P 412-421
%@ 1832-4274
%X Abstract Disorders of eye development such as microphthalmia and anophthalmia (small and absent eyes respectively), anterior segment dysgenesis where there may be pupillary and iris anomalies, and associated cataract and glaucoma, often lead to visual impairment or blindness. Currently treatment options are limited, as much is unknown about the molecular pathways that control normal eye development and induce the aberrant processes that lead to ocular defects. Mutation detection rates in most of the known genes are generally low, emphasizing the genetic heterogeneity of developmental ocular defects. Identification of the disease genes in these conditions improves the clinical information available for affected individuals and families, and provides new insights into the underlying biological processes for facilitation of better treatment options. Investigation of chromosomal rearrangements associated with an ocular phenotype has been especially powerful for disease gene identification. Molecular characterization of such rearrangements, which pinpoints the region by physically disrupting the causative gene or its regulatory sequences, allows for rapid elucidation of underlying genetic factors that contribute to the phenotype. Genes including PAX6, PITX2, FOXC1, MAF, TMEM114, SOX2, OTX2 and BMP4 have been identified in this way to be associated with developmental eye disorders. More recently, new methods in chromosomal analysis such as comparative genomic hybridization (CGH) microarray, have also enhanced our ability in disease gene identification.
%Z FOR Codes: 111301


%0 Journal Article
%~ PubMed
%A Lewis, Samara L
%A Khoo, Poh-Lynn
%A De Young, R Andrea
%A Steiner, Kirsten
%A Wilcock, Chris
%A Mukhopadhyay, Mahua
%A Westphal, Heiner
%A Jamieson, Robyn V
%A Robb, Lorraine
%A Tam, Patrick P L
%T Dkk1 and Wnt3 interact to control head morphogenesis in the mouse.
%B Development (Cambridge)
%D 2008
%C United Kingdom
%I The Compant of Biologists Ltd
%V 135
%N 10
%P 1791-1801
%@ 0950-1991
%X Loss of Dkk1 results in ectopic WNT/beta-catenin signalling activity in the anterior germ layer tissues and impairs cell movement in the endoderm of the mouse gastrula. The juxtaposition of the expression domains of Dkk1 and Wnt3 is suggestive of an antagonist-agonist interaction. The downregulation of Dkk1 when Wnt3 activity is reduced reveals a feedback mechanism for regulating WNT signalling. Compound Dkk1;Wnt3 heterozygous mutant embryos display head truncation and trunk malformation, which are not found in either Dkk1(+/-) or Wnt3(+/-) embryos. Reducing the dose of Wnt3 gene in Dkk1(-/-) embryos partially rescues the truncated head phenotype. These findings highlight that head development is sensitive to the level of WNT3 signalling and that DKK1 is the key antagonist that modulates WNT3 activity during anterior morphogenesis.
%Z FOR Codes: 110311


%0 Journal Article
%~ PubMed
%A Kondo, Mari
%A Gray, Laura J
%A Pelka, Gregory J
%A Christodoulou, John
%A Tam, Patrick P L
%A Hannan, Anthony J
%T Environmental enrichment ameliorates a motor coordination deficit in a mouse model of Rett syndrome--Mecp2 gene dosage effects and BDNF expression.
%B The European journal of neuroscience
%D 2008
%C UK
%I Blackwell Publishing Ltd
%V 27
%N 12
%P 3342-50
%@ 0953-816X
%X Rett syndrome, commonly associated with mutations of the methyl CpG-binding protein 2 (MECP2) gene, is characterised by an apparently normal early postnatal development followed by deterioration of acquired cognitive and motor coordination skills in early childhood. To evaluate whether environmental factors may influence the disease outcome of Rett syndrome, we tested the effect of environmental enrichment from 4 weeks of age on the behavioural competence of mutant mice harboring a Mecp2 (tm1Tam)-null allele. Our findings show that enrichment improves motor coordination in heterozygous Mecp2+/- females but not Mecp2-/y males. Standard-housed Mecp2+/- mice had an initial motor coordination deficit on the accelerating rotarod, which improved with training then deteriorated in subsequent weeks. Enrichment resulted in a significant reduction in this coordination deficit in Mecp2+/- mice, returning the performance to wild-type levels. Brain-derived neurotrophic factor (BDNF) protein levels were 75 and 85% of wild-type controls in standard-housed and environmentally enriched Mecp2+/- cerebellum, respectively. Mecp2-/y mice showed identical deficits of cerebellar BDNF (67% of wild-type controls) irrespective of their housing environment. Our findings demonstrate a positive impact of environmental enrichment in a Rett syndrome model; this impact may be dependent on the existence of one functional copy of Mecp2.
%Z FOR Codes: 110999


%0 Journal Article
%~ PubMed
%A Franklin, Vanessa
%A Khoo, Poh Lynn
%A Bildsoe, Heidi
%A Wong, Nicole
%A Lewis, Samara
%A Tam, Patrick P L
%T Regionalisation of the endoderm progenitors and morphogenesis of the gut portals of the mouse embryo.
%B Mechanisms of Development
%D 2008
%C Ireland
%I Elsevier Ireland
%V 125
%N 7
%P 587-600
%@ 1872-6356
%X This fate-mapping study reveals that the progenitors of all major parts of the embryonic gut are already present in endoderm of the early-head-fold to early-somite stage (1-9 somites) mouse embryo. The anterior endoderm contributes primarily to the anterior intestinal portal of the early-organogenesis stage (16-19 somites) embryo. Endoderm cells around and lateral to the node are allocated to the open "midgut" region of the embryonic gut. The posterior (post-nodal) endoderm contributes not only to the posterior intestinal portal but also the open "midgut". Descendants of the posterior endoderm span a length of the gut from the level of the 3rd-5th somites to the posterior end of the embryonic gut. The formation of the anterior and posterior intestinal portals is accompanied by similar repertoires of morphogenetic tissue movement. We also discovered that cells on contralateral sides of the anterior endoderm are distributed asymmetrically to the dorsal and ventral sides of the anterior intestinal portal, heralding the acquisition of laterality by the embryonic foregut.
%Z FOR Codes: 60803


%0 Journal Article
%~ PubMed
%A Fossat, Nicolas
%A Pfister, Sabine
%A Tam, Patrick P L
%T A transcriptome landscape of mouse embryogenesis.
%B Developmental Cell
%D 2007
%C United States
%I Cell Press
%V 13
%N 6
%P 761-762
%@ 1534-5807
%X Coordinated regulation of genetic activity underpins formation of the body plan and morphogenesis of embryonic structures. In this issue of Developmental Cell, Mitiku and Baker describe a chronological series of transcriptomes of postimplantation mouse embryos at gastrulation and early organogenesis, providing a valuable resource for studying the dynamics of both genome-wide and gene-specific transcriptional activities that accompany mouse embryogenesis.
%Z FOR Codes: 60802


%0 Journal Article
%~ PubMed
%A Tam, Patrick
%A Lovell-Badge, Robin
%T Anne McLaren 1927-2007.
%B Cell
%D 2007
%C United States
%I Cell Press
%V 130
%N 2
%P 201-213
%@ 0092-8674
%X 
%Z FOR Codes: 111799


%0 Journal Article
%~ PubMed
%A Jamieson, Robyn V
%A Farrar, Nicola
%A Stewart, Katrina
%A Perveen, Rahat
%A Mihelec, Marija
%A Carette, Martin
%A Grigg, John R
%A McAvoy, John W
%A Lovicu, Frank J
%A Tam, Patrick P L
%A Scambler, Peter
%A Lloyd, I Christopher
%A Donnai, Dian
%A Black, Graeme C M
%T Characterization of a familial t(16;22) balanced translocation associated with congenital cataract leads to identification of a novel gene, TMEM114, expressed in the lens and disrupted by the translocation.
%B Human mutation
%D 2007
%C DIV JOHN WILEY & SON
%I Wiley-Liss
%V 28
%N 10
%P 968-977
%@ 1098-1004
%X Molecular characterization of chromosomal rearrangements is a powerful resource in identification of genes associated with monogenic disorders. We describe the molecular characterization of a balanced familial chromosomal translocation, t(16;22)(p13.3;q11.2), segregating with congenital lamellar cataract. This led to the discovery of a cluster of lens-derived expressed sequence tags (ESTs) close to the 16p13.3 breakpoint. This region harbors a locus associated with cataract and microphthalmia. Long-range PCR and 16p13.3 breakpoint sequencing identified genomic sequence in a human genome sequence gap, and allowed identification of a novel four-exon gene, designated TMEM114, which encodes a predicted protein of 223 amino acids. The breakpoint lies in the promoter region of TMEM114 and separates the gene from predicted eye-specific upstream transcription factor binding sites. There is sequence conservation among orthologs down to zebrafish. The protein is predicted to contain four transmembrane domains with homology to the lens intrinsic membrane protein, LIM2 (also known as MP20), in the PMP-22/EMP/MP20 family. TMEM114 mutation screening in 130 congenital cataract patients revealed missense mutations leading to the exchange of highly-conserved amino acids in the first extracellular domain of the protein (p.I35T, p.F106L) in two separate patients and their reportedly healthy sibling and mother, respectively. In the lens, Tmem114 shows expression in the lens epithelial cells extending into the transitional zone where early fiber differentiation occurs. Our findings implicate dysregulation of expression of this novel human gene, TMEM114, in mammalian cataract formation.
%Z FOR Codes: 111301


%0 Journal Article
%~ PubMed
%A Franklin, Vanessa J
%A Bildsoe, Heidi
%A Tam, Patrick P L
%T Fate-Mapping Technique: Grafting Fluorescent Cells into Gastrula-Stage Mouse Embryos at 7-7.5 Days Post-coitum.
%B CSH protocols
%D 2007
%C United States
%I Cold Spring Harbor Laboratory Press
%V 2007
%N 
%P pdb.prot4892
%@ 1559-6095
%X INTRODUCTIONAnalysis of the developmental fate of cell populations in different parts of the embryo enables the construction of fate maps. These reveal the organization of the body plan and can presage the expression of molecular characteristics of cell lineages and the formation of body parts. The efficacy of fate-mapping techniques is critically dependent on their ability to track the cells and all their descendants without compromising the development of the embryo. Cell grafting involves isolating a population of genetically tagged cells from a transgenic embryo and grafting them to a defined site in a nontransgenic host embryo. Tissue colonization is analyzed using a genetic tag (e.g., a fluorescent protein that can be visualized noninvasively) that allows tracking of the transplanted cells and their descendants in the host embryo throughout development in culture. Alternatively, a lacZ transgene can be used to localize graft-derived cells histologically. Differentiation of the graft-derived cells can be studied by examining the expression of molecular markers by in situ hybridization of gene transcripts or immunohistochemical detection of lineage-specific proteins. This protocol describes how to graft cells isolated from a donor embryo into the germ layer of a wild-type host mouse embryo at 7-7.5 days post-coitum (dpc).
%Z FOR Codes: 69999


%0 Journal Article
%~ PubMed
%A Khoo, P-L
%A Franklin, V J
%A Tam, P P L
%T Fate-Mapping Technique: Targeted Whole-Embryo Electroporation of DNA Constructs into the Germ Layers of Mouse Embryos 7-7.5 Days Post-coitum.
%B CSH protocols
%D 2007
%C United States
%I Cold Spring Harbor Laboratory Press
%V 2007
%N 
%P pdb.prot4893
%@ 1559-6095
%X INTRODUCTIONFate maps reveal body plan organization and presage the expression of molecular characteristics of cell lineages and formation of body parts. This protocol targets DNA expression constructs into the germ layers of gastrula-stage mouse embryos by focal electroporation. Plasmids utilizing a promoter that drives widespread, non-lineage-restricted expression of transgenes are introduced to cells in defined germ layer regions by whole-embryo electroporation. Germ-layer cells are exposed to the DNA by microinjecting the plasmids into the proamniotic cavity (ectoderm) or directly into the intercellular space of the mesenchyme (mesoderm), or by incubating the embryo in the DNA solution (endoderm). Electroporation is performed on whole embryos in vitro by electric current-mediated permeation of the cell membrane, which allows DNA adsorbed to cell surfaces to enter the cells. A point electrode is used to focus the electric field to the intended site of electroporation and a plate electrode is used to generate the current at an effective voltage low enough to minimize damage to the embryonic tissue. Expression of the transgene can be used to track the fate and movement of cells and the cDNA to study the functional consequences of overexpression of genes during embryonic development in vitro.
%Z FOR Codes: 69999


%0 Journal Article
%~ PubMed
%A Bildsoe, Heidi
%A Franklin, Vanessa
%A Tam, Patrick P L
%T Fate-mapping technique: using carbocyanine dyes for vital labeling of cells in gastrula-stage mouse embryos cultured in vitro.
%B CSH protocols
%D 2007
%C United States
%I Cold Spring Harbor Laboratory Press
%V 2007
%N 
%P pdb.prot4915
%@ 1559-6095
%X INTRODUCTIONThe allocation of different progenitor populations to embryonic structures can be visualized by tracking the distribution of cells to specific tissues in the live embryo. A critical prerequisite for cell tracking is to identify unambiguously the progenitors and their descendants during morphogenesis. This can be achieved by using molecular markers that are expressed from transgenes integrated into the genome or as episomal DNA constructs, or by tagging the cells with exogenous markers that are incorporated into the cell membrane or cytoplasmic components of the cells. These labels can be introduced by dye-labeling the membrane, injecting marker enzyme into the cytoplasm, or integrating reporter constructs by transfection or electroporation. This protocol describes how to label cells in the endoderm (which, at this stage of development, is the superficial tissue layer) of live mouse embryos at 7.0-7.5 days post-coitum (dpc), using two carbocyanine dyes (DiI and DiO).
%Z FOR Codes: 69999


%0 Journal Article
%~ PubMed
%A Pfister, Sabine
%A Steiner, Kirsten A
%A Tam, Patrick P L
%T Gene expression pattern and progression of embryogenesis in the immediate post-implantation period of mouse development.
%B Gene expression patterns : GEP
%D 2007
%C Netherlands
%I Elsevier BV
%V 7
%N 5
%P 558-5573
%@ 1567-133X
%X During development of the mouse conceptus from implantation to the early gastrula stage, a multitude of genes encoding structural proteins, transcription factors and components of signalling pathways are expressed in the extraembryonic and embryonic tissues derived from the trophectoderm and the inner cell mass. Some genes are expressed widely in the extraembryonic ectoderm, the visceral endoderm or the epiblast, while others display more restricted expression domains in these tissues or are expressed upon the specification of the germ layers at gastrulation. Overall, the developmental changes in gene expression mirror key events of embryogenesis, and reveal the regionalization of signalling activity and the emergence of tissue patterning.
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Tam, Patrick P L
%A Loebel, David A F
%T Gene function in mouse embryogenesis: get set for gastrulation.
%B Nature reviews. Genetics
%D 2007
%C United Kingdom
%I Nature Publishing Group
%V 8
%N 5
%P 368-381
%@ 1471-0056
%X During early mouse embryogenesis, temporal and spatial regulation of gene expression and cell signalling influences lineage specification, embryonic polarity, the patterning of tissue progenitors and the morphogenetic movement of cells and tissues. Uniquely in mammals, the extraembryonic tissues are the source of signals for lineage specification and tissue patterning. Here we discuss recent discoveries about the lead up to gastrulation, including early manifestations of asymmetry, coordination of cell and tissue movements and the interactions of transcription factors and signalling activity for lineage allocation and germ-layer specification.
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Lewis, Samara L
%A Khoo, Poh-Lynn
%A Andrea De Young, R
%A Bildsoe, Heidi
%A Wakamiya, Maki
%A Behringer, Richard R
%A Mukhopadhyay, Mahua
%A Westphal, Heiner
%A Tam, Patrick P L
%T Genetic interaction of Gsc and Dkk1 in head morphogenesis of the mouse.
%B Mechanisms of Development
%D 2007
%C Ireland.
%I Elsevier Ireland Ltd
%V 124
%N 2
%P 157-165
%@ 0925-4773
%X Mouse embryos lacking Gsc and Dkk1 function display severe deficiencies in craniofacial structures which are not found in either Dkk1 homozygous null or Gsc homozygous null mutant embryos. Loss of Gsc has a dosage-related effect on the severity of head truncation phenotype in Dkk1 heterozygous embryos. The synergistic effect of these mutations in enhancing head truncation provides direct evidence of a genetic interaction between Gsc and Dkk1, which display overlapping expression in the prechordal mesoderm. In the absence of Gsc activity, the expression of Dkk1, WNT genes and a transgenic reporter for WNT signalling are altered. Our results show that Gsc and Dkk1 functions are non-redundant in the anterior mesendoderm for normal anterior development and Gsc may influence Wnt signalling as a negative regulator.
%Z FOR Codes: 60802


%0 Journal Article
%~ PubMed
%A Tam, Patrick P L
%A Khoo, Poh-Lynn
%A Lewis, Samara L
%A Bildsoe, Heidi
%A Wong, Nicole
%A Tsang, Tania E
%A Gad, Jacqueline M
%A Robb, Lorraine
%T Sequential allocation and global pattern of movement of the definitive endoderm in the mouse embryo during gastrulation.
%B Development (Cambridge, England)
%D 2007
%C United Kingdom
%I The Company of Biologists Ltd.
%V 134
%N 2
%P 251-260
%@ 0950-1991
%X During mouse gastrulation, endoderm cells of the dorsal foregut are recruited ahead of the ventral foregut and move to the anterior region of the embryo via different routes. Precursors of the anterior-most part of the foregut and those of the mid- and hind-gut are allocated to the endoderm of the mid-streak-stage embryo, whereas the precursors of the rest of the foregut are recruited at later stages of gastrulation. Loss of Mixl1 function results in reduced recruitment of the definitive endoderm, and causes cells in the endoderm to remain stationary during gastrulation. The observation that the endoderm cells are inherently unable to move despite the expansion of the mesoderm in the Mixl1-null mutant suggests that the movement of the endoderm and the mesoderm is driven independently of one another.
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Tam, Patrick Pl
%A Loebel, David Af
%A Tanaka, Satomi S
%T Building the mouse gastrula: signals, asymmetry and lineages.
%B Current opinion in genetics & development
%D 2006
%C United Kingdom
%I Elsevier Ltd.
%V 16
%N 4
%P 419-25
%@ 0959-437X
%X The mouse embryo is built by assembling the progenitors of various tissue types into a body plan. Early postimplantation development involves the establishment of anatomical asymmetries and regionalized gene expression in the conceptus, the specification of tissue lineages, and the coordination of cell movement for correct positioning of the lineage progenitors before and at gastrulation. Recent findings reveal that Wnt and Tgfbeta signalling function is instrumental in delineating the anterior-posterior embryonic axis by defining the site of primitive streak formation and by directing the movement of the visceral endoderm. These signalling activities are also required for the specification of anterior and posterior fates of the epiblast cells and for the induction and navigation of the primordial germ cells.
%Z FOR Codes: 111401 60403


%0 Journal Article
%~ Isi
%A Willcock, C.
%A Grigg, J.
%A Wilson, M.
%A Tam, P.
%A Billson, F.
%A Jamieson, R.
%T Congenital iris ectropion as an indicator of variant aniridia.
%B British Journal of Ophthalmology
%D 2006
%C Australia
%I Blackwell Publishing Asia
%V 90
%N 5
%P 658-659
%@ 0007-1161
%X 
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Lewis, Samara L
%A Tam, Patrick P L
%T Definitive endoderm of the mouse embryo: Formation, cell fates, and morphogenetic function.
%B Developmental dynamics : an official publication of the American Association of Anatomists
%D 2006
%C United States
%I John Wiley & Sons, Inc.
%V 235
%N 9
%P 2315-29
%@ 1058-8388
%X The endoderm is one of the primary germ layers but, in comparison to ectoderm and mesoderm, has received less attention. The definitive endoderm forms during gastrulation and replaces the extraembryonic visceral endoderm. It participates in the complex morphogenesis of the gut tube and contributes to the associated visceral organs. This review highlights the role of the definitive endoderm as a source of patterning cues for the morphogenesis of other germ-layer tissues, such as the anterior neurectoderm and the pharyngeal region, and also emphasizes the intricate patterning that the endoderm itself undergoes enabling the acquisition of regionalized cell fates.
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Nolen, Leisha D
%A Amor, David
%A Haywood, Ashley
%A St Heaps, Luke
%A Willcock, Chris
%A Mihelec, Marija
%A Tam, Patrick
%A Billson, Frank
%A Grigg, John
%A Peters, Greg
%A Jamieson, Robyn V
%T Deletion at 14q22-23 indicates a contiguous gene syndrome comprising anophthalmia, pituitary hypoplasia, and ear anomalies.
%B American journal of medical genetics. Part A
%D 2006
%C United States
%I John Wiley & Sons, Inc.
%V 140
%N 16
%P 1711-8
%@ 1552-4825
%X Anophthalmia and pituitary gland hypoplasia are both debilitating conditions where the underlying genetic defect is unknown in the majority of cases. We identified a patient with bilateral anophthalmia and absence of the optic nerves, chiasm and tracts, as well as pituitary gland hypoplasia and ear anomalies with a de novo apparently balanced chromosomal translocation, 46,XY,t(3;14)(q28;q23.2). Translocation breakpoint analysis using FISH and high-resolution microarray comparative genomic hybridization (CGH) has identified a 9.66 Mb deleted region on the long arm of chromosome 14 which includes the genes BMP4, OTX2, RTN1, SIX6, SIX1, and SIX4. Three other patients with interstitial deletions involving 14q22-23 have been described, all with bilateral anophthalmia, pituitary abnormalities, ear anomalies, and a facial phenotype similar to our patient. OTX2 is involved in ocular developmental defects, and the severity of the ocular phenotype in our patient and the other 14q22-23 deletion patients, suggests this genomic region harbors other gene/s involved in ocular development. BMP4 haploinsufficiency is predicted to contribute to the ocular phenotype on the basis of its expression pattern and observed murine mutant phenotypes. In addition, deletion of BMP4 and SIX6 is likely to contribute to the abnormal pituitary development, and SIX1 deletion may contribute to the ear and other craniofacial features. This indicates that contiguous gene deletion may contribute to the phenotypic features in the 14q22-23 deletion patients.
%Z FOR Codes:


%0 Journal Article
%~ Isi
%A Tanaka, S. S.
%A Yamaguchi, Y. L.
%A Tam, P. P. L.
%T Experimental approaches to study gene function in whole mouse embryo and fetal ovary in vitro.
%B Transgenic Research
%D 2006
%C Netherlands
%I Springer-Verlag Dordrecht
%V 15
%N 6
%P 778-778
%@ 0962-8819
%X 
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Duffy, Shannon L
%A Steiner, Kirsten A
%A Tam, Patrick P L
%A Boyd, Andrew W
%T Expression analysis of the Epha1 receptor tyrosine kinase and its high-affinity ligands Efna1 and Efna3 during early mouse development.
%B Gene expression patterns : GEP
%D 2006
%C Netherlands
%I Elsevier BV
%V 6
%N 7
%P 719-23
%@ 1567-133X
%X Interaction of Eph receptor tyrosine kinases with their membrane bound ephrin ligands initiates bidirectional signaling events that regulate cell migratory and adhesive behavior. Whole-mount in situ hybridization revealed overlapping expression of the Epha1 receptor and its high-affinity ligands ephrin A1 (Efna1) and ephrin A3 (Efna3) in the primitive streak and the posterior paraxial mesoderm during early mouse development. These results show complex and dynamic expression for all three genes with expression domains that are successively complementary, overlapping, and divergent.
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Yamaguchi, Yasuka L
%A Tanaka, Satomi S
%A Kasa, Miyuki
%A Yasuda, Kunio
%A Tam, Patrick P L
%A Matsui, Yasuhisa
%T Expression of low density lipoprotein receptor-related protein 4 (Lrp4) gene in the mouse germ cells.
%B Gene expression patterns : GEP
%D 2006
%C Netherlands
%I Elsevier BV
%V 6
%N 6
%P 607-12
%@ 1567-133X
%X The low density lipoprotein receptor-related protein 4 gene (Lrp4) was identified by subtractive screening of cDNAs of the migratory primordial germ cells (PGCs) of E8.5-9.5 embryo and E3.5 blastocysts. Lrp4 is expressed in PGCs in the hindgut and the dorsal mesentery of E9.5 embryos, and in germ cells in the genital ridges of male and female E10.5-13.5 embryos. Lrp4 is also expressed in spermatogonia of the neonatal and adult testes and in the immature oocytes and follicular cells of the adult ovary. The absence of Lrp4 expression in the blastocyst, embryonic stem cells and embryonic germ cells suggests the Lrp4 is a molecular marker that distinguishes the germ cells from embryo-derived pluripotent stem cells.
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%0 Journal Article
%~ PubMed
%A Pelka, Gregory J
%A Watson, Catherine M
%A Radziewic, Tania
%A Hayward, Melinda
%A Lahooti, Hooshang
%A Christodoulou, John
%A Tam, Patrick P L
%T Mecp2 deficiency is associated with learning and cognitive deficits and altered gene activity in the hippocampal region of mice.
%B Brain; a journal of neurology
%D 2006
%C United Kingdom
%I Oxford University Press
%V 129
%N Pt 4
%P 887-98
%@ 1460-2156
%X Rett syndrome (RTT) is a debilitating neurological condition associated with mutations in the X-linked MECP2 gene, where apparently normal development is seen prior to the onset of cognitive and motor deterioration at 6-18 months of life. A targeted deletion of the methyl-CpG-binding domain (MBD) coding region and disruption of mRNA splicing was introduced in the mouse, resulting in a complete loss of Mecp2 transcripts and protein. Postnatal comparison of XO and XY mutant Mecp2 allele-containing null mice revealed similar effects on mouse growth and viability, suggesting that phenotypic manifestations are not modulated by the Y-chromosome. Further assessment of Mecp2-null XY mice highlighted cerebellar and hippocampal/amygdala-based learning deficits in addition to reduced motor dexterity and decreased anxiety levels. Brain tissues containing the hippocampal formation of XY Mecp2-null mice also displayed significant changes in genetic activity, which are related to the severity of the mutant phenotype.
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%0 Journal Article
%~ PubMed
%A Yamaguchi, Yasuka L
%A Tanaka, Satomi S
%A Yasuda, Kunio
%A Matsui, Yasuhisa
%A Tam, Patrick P L
%T Stage-specific Importin13 activity influences meiosis of germ cells in the mouse.
%B Developmental biology
%D 2006
%C United States
%I Academic Press
%V 297
%N 2
%P 350-60
%@ 0012-1606
%X Importin-mediated transport of cargoes is known to be a key mechanism for nucleo-cytoplasmic trafficking of molecules. Ipo13, which is a member of Importin-beta gene family, encodes two transcripts by utilizing different transcription start sites. In the mouse, the full-length transcript (L-Ipo13) is expressed in the primordial germ cells in the embryo and is later expressed predominantly at the pachytene phase of meiosis in both male and female germ cells. The shorter transcript (TS-Ipo13) is only expressed in the germ cells in the adult testis. Activity of L-Ipo13, but not TS-Ipo13, mediates the nuclear accumulation of ubiquitin-conjugating enzyme 9 (UBC9), a cargo of human IPO13. This finding is consistent with the progressive accumulation of UBC9 in the nucleus of the meiotic germ cells after the onset of L-Ipo13 expression. Following siRNA knockdown of IPO13 activity in the fetal ovary, fewer germ cells are found to progress to the late-pachytene stage of meiosis and nuclear accumulation of UBC9 is reduced. Our findings strongly implicate a stage-specific role of IPO13 in nuclear-cytoplasmic translocation of cargoes that accompanies meiotic differentiation of the mouse germ cells.
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