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.

Establish the food intake control system in zebrafish to analyze human obesity candidate genes

Primary supervisor: Silke Rinkwitz

Lifestyle is thought to have a critical role in the increasing number of obese people. Recent genetic studies however have led to the conclusion that unlimited access to food is should be seen as a permissive factor for the genetically predisposed. Most prominently, obesity predisposition can be related to genes that regulate energy balance. Such genes code for molecules acting on centers in the brain that are involved in the control of food intake. Examples are the functions of leptin, a hormone made in adipose tissue, and its receptor, located in the hypothalamus. When the leptin receptor becomes activated it reduces hunger.

We use the zebrafish as a developmental vertebrate model organism to elucidate the role of hypothalamic obesity candidate genes. The zebrafish is a well-established model organism for forward and reverse genetic approaches. External development, large numbers of eggs, transparency of the embryos and larvae and rapid differentiation (eating behavior starts at 5 days post fertilization) make this laboratory organism especially suitable for studying the role of genes in physiological or behavioral processes.

Our projects aim to characterize zebrafish versions of genes that control energy homeostasis in humans and that are active in the zebrafish hypothalamus and brainstem. A selection of genes marking the food intake control system in zebrafish as well as three obesity candidate genes need to be analyzed for their sites of activity in the adult zebrafish brain. Once the expression patterns are established the knowledge can be applied to characterize the distribution of fluorescent proteins that are activated by the regulatory control regions of these genes in transgenic zebrafish used as live markers. Such studies will establish zebrafish as a vertebrate model system of obesity and will further shed light on human obesity candidate genes and their disease causing mechanisms.



Discipline: Anatomy & Histology
Co-supervisors: Tom Becker
Keywords: Obesity & overweight, Brain, Neurobiology