Sex determination is a fundamental developmental decision in which the bipotential gonad is directed into specific pathways of male or female development. Despite the central importance of this process, there is still much to learn about its underlying molecular mechanisms. Our long term goal is to discover and characterize the gene regulatory network responsible for this central developmental switch in vertebrates. We have three specific aims: 1) to use the extensive genomic resources we have developed for cichlid fishes to complete the genetic mapping of male heterogametic (XY) sex determining loci on LGs 1 and 7, and female heterogametic (WZ) systems on LGs 3 and 5. Characterization of the critical map interval for each locus is the first step in identifying the top-level regulatory genes in each species. 2) to use quantitative PCR and in situ hybridization to quantify the normal pattern of gene expression in the developing gonads of our model system, the Nile tilapia. We will then examine the spatial and temporal expression of candidate sex-determining genes within this framework. 3) to quantify patterns of gene expression in response to both natural perturbations (e.g. the natural differences among the four sex-determining systems) and the experimental upregulation of gene expression by means of transgenesis. This combination of natural and experimental manipulations will allow us to probe the structure of the regulatory network in detail. Together, these experiments will provide insights about the gene networks regulating vertebrate sex determination. How many genes can control the sexual fate of vertebrates? Do the nodes which become top-level regulators of sex determination have unique characteristics? Does the sex- determining pathway have a modular organization, and if so, what is the relationship of the top-level regulators to these modules? This work will also facilitate the identification of genes which contribute to aberrant sexual development and gonadal tumors in humans. Project Narrative: Defects in gonadal specification and differentiation are among the most common developmental defects, resulting in partial sex reversal, infertility and various cancers. This project will characterize portions of the complex genetic control network responsible for sex determination and gonadal development that are shared among vertebrate species. This knowledge will contribute to the discovery of new therapies for these defects in humans.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD058635-04
Application #
8137848
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Taymans, Susan
Project Start
2008-09-29
Project End
2012-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
4
Fiscal Year
2011
Total Cost
$285,120
Indirect Cost
Name
University of Maryland College Park
Department
Biology
Type
Schools of Earth Sciences/Natur
DUNS #
790934285
City
College Park
State
MD
Country
United States
Zip Code
20742
Loh, Yong-Hwee E; Bezault, Etienne; Muenzel, Frauke M et al. (2013) Origins of shared genetic variation in African cichlids. Mol Biol Evol 30:906-17
Lee, Bo-Young; Coutanceau, Jean-Pierre; Ozouf-Costaz, Catherine et al. (2011) Genetic and physical mapping of sex-linked AFLP markers in Nile tilapia (Oreochromis niloticus). Mar Biotechnol (NY) 13:557-62
Mazzuchelli, Juliana; Yang, Fengtang; Kocher, Thomas D et al. (2011) Comparative cytogenetic mapping of Sox2 and Sox14 in cichlid fishes and inferences on the genomic organization of both genes in vertebrates. Chromosome Res 19:657-67
Fujimura, Koji; Conte, Matthew A; Kocher, Thomas D (2011) Circular DNA intermediate in the duplication of Nile tilapia vasa genes. PLoS One 6:e29477
Fujimura, Koji; Kocher, Thomas D (2011) Tol2-mediated transgenesis in tilapia (Oreochromis niloticus). Aquaculture 319:342-346
Ser, Jennifer R; Roberts, Reade B; Kocher, Thomas D (2010) Multiple interacting loci control sex determination in lake Malawi cichlid fish. Evolution 64:486-501
Shirak, Andrey; Grabherr, Manfred; Di Palma, Federica et al. (2010) Identification of repetitive elements in the genome of Oreochromis niloticus: tilapia repeat masker. Mar Biotechnol (NY) 12:121-5
Ferreira, I A; Poletto, A B; Kocher, T D et al. (2010) Chromosome evolution in African cichlid fish: contributions from the physical mapping of repeated DNAs. Cytogenet Genome Res 129:314-22
Soler, Lucile; Conte, Matthew A; Katagiri, Takayuki et al. (2010) Comparative physical maps derived from BAC end sequences of tilapia (Oreochromis niloticus). BMC Genomics 11:636
Lee, Bo-Young; Howe, Aimee E; Conte, Matthew A et al. (2010) An EST resource for tilapia based on 17 normalized libraries and assembly of 116,899 sequence tags. BMC Genomics 11:278

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