Developmental Neurobiology & Genomics Laboratory

Lab head: Thomas Becker
Location: Brain and Mind Research Insititute, 100 Mallet Street, Building K, Level 3, Camperdown 2050

Professor Thomas Becker and Dr Silke Rinkwitz manage a team of six students and researchers investigating gene regulatory mechanisms that constitute risk factors in the development of human disease. Through computational analyses, enhancer detection and transgenic tools in zebrafish, the team investigates the function of human genomic regions and genes that have been implicated in X-linked neurological diseases, hypothalamic obesity and Karsch Neugebauer Syndrome.

Lab members: Prof. Thomas Becker (Head of the Laboratory), Dr. Silke Rinkwitz (Senior Researcher), Dr. Anna Kommisarczuk (Postdoctoral Fellow), Dr. Minaka Ishibashi (Postdoctoral Fellow), Dr. Elizabeth Manning (Research Assistant), David Maley (Fish Facility Manager), Bethany Stavert (Honours Student), Abbas Hussein (Master Student)
Research approach equipment: Transgenic zebrafish are used as vertebrate models to elucidate the roles of genes in human disease. With its transparency and external development, a sequenced genome and a nervous system comparable to that of humans, the zebrafish is an excellent system for analyzing and manipulating gene function. A 1000 tank zebrafish facility, microscopes, injection equipment and a molecular biological laboratory provide the infrastructure to create and work with genetically modified fish.

Punnamoottil, B., Herrmann, C., Anaya, J. P., D'Aniello, S., Garcia-Fernàndez, J., Akalin, A.,  Becker, T. S and Rinkwitz, S. (2010). Cis-regulatory characterization of sequence conservation surrounding the Hox4 genes. Dev. Biol., 340 (2), 269-282.

Ragvin A, Moro E, Fredman D, Navratilova P, Drivenes Ø, Engström PG, Alonso ME, Mustienes Ede L, Skarmeta JL, Tavares MJ, Casares F, Manzanares M, van Heyningen V, Molven A, Njølstad PR, Argenton F, Lenhard B, Becker TS. (2010). Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX, SOX4, and IRX3. Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):775-80.

Navratilova, P., Becker, T. (2009). Genomic regulatory blocks in vertebrates and implications in human disease. Briefings in functional genomics & proteomics; 8:333-42.

Amsterdam, A., Lai, K., Komisarczuk, A., Becker, T., Bronson, R., Hopkins, N., Lees, J. (2009). Zebrafish Hagoromo mutants up-regulate fgf8 postembryonically and develop neuroblastoma. Molecular Cancer Research; 7:841-850.

Navratilova, P., Fredman, D., Hawkins, T., Turner, K., Lenhard, B., Becker, T. (2009). Systematic human/zebrafish comparative identification of cis-regulatory activity around vertebrate developmental transcription factor genes. Developmental biology; 327:526-540.

Ma, L. H., Punnamoottil, B., Rinkwitz, S., Baker, R. (2009). Mosaic hoxb4a neuronal pleiotropism in zebrafish caudal hindbrain. PLoS One. Jun 17;4(6):e5944.

Punnamoottil, B., Kikuta, H., Pezeron, G., Erceg, J., Becker, T. S., Rinkwitz, S. (2008). Enhancer detection in zebrafish permits the identification of neuronal subtypes that express Hox4 paralogs. Dev. Dyn., 237(8):2195-2208.

Kikuta, H., Fredman, D., Rinkwitz, S., Lenhard, B., Becker T. S (2007). Retroviral enhancer detection insertions in zebrafish combined with comparative genomics reveal genomic regulatory blocks - a fundamental feature of vertebrate genomes. Genome Biol. 8 (Suppl 1): S4.

Kikuta, H., Laplante, M., Navratilova, P., Komisarczuk, A., Engström, P., Fredman, D., Akalin, A., Caccamo, M., Sealy, I., Howe, K., Ghislain, J., Pezeron, G., Mourrain, P., Ellingsen, S., Oates, A., Thisse, C., Thisse, B., Foucher, I., Adolf, B., Geling, A., Lenhard, B., Becker, T. (2007). Genomic regulatory blocks encompass multiple neighboring genes and maintain conserved synteny in vertebrates. Genome research; 17:545-555.

Creation of transgenic zebrafish models to analyze the mechanisms underlying X-chromosome linked neurological diseases

Primary supervisor: Silke Rinkwitz

As part of an international consortium, our lab focuses on the genetic basis underlying X-linked neurological diseases. Current estimates suggest close to 100 loci causing X-linked intellectual disability (XLID), as well as numerous loci involved in demyelinating diseases, epilepsy, autism and spastic paraplegia and some eye anomalies. Because of their relatively high prevalence and their social importance, the genetic defects underlying XLID are actively pursued at many levels. Severe XLID is often caused by chromosomal aberrations or defects in specific genes, while milder forms are thought to result from interaction of multiple genes and environmental factors.

Since the gross brain anatomy and the neurotransmitter systems as well as the genetic mechanisms in brain development are well conserved between human and zebrafish, we use the zebrafish as a model system to analyze the function and regulation of disease genes. An external, rapid development, transparent embryos and a sequenced genome established this model especially for the genetic study of developmental processes and diseases.

We use transgenic approaches for analyzing X-linked neurological disease genes. We create zebrafish lines with genomic modifications that can be used to reveal the sites of activity of the gene of interest and also, for functional analyses, to modify the activity of the gene in living embryos/larvae.

Within this project reporter gene DNA constructs and expression vectors will be created and subsequently injected into fertilized zebrafish eggs. Molecular biological and microinjection techniques as well as work with zebrafish are required. Injected fish will be grown in the facility until fertile and then microscopically screened and analyzed. The project is suitable for a student with interest in genetics and brain development and who likes molecular biological bench work and has manual dexterity for doing micromanipulations.

Discipline: Physiology
Co-supervisors: Tom Becker
Keywords: Genetic diseases, Brain, developmental neurobiology