Normal human gonad development can be adversely affected in utero by unknown genetic and environmental factors leading to testis dysgeneration syndrome and polycystic ovarian syndrome. In mammals, the Y-chromosome gene SRY initiates an incompletely understood genetic network that directs the gonad to become a testis, while competing genes direct ovary development. Non-mammalian vertebrates use similar down-stream networks, but primary sex determination (SD) genes differ. Additionally, in some species, environmental factors such as temperature or nutrition bias SD. Our broad objective is to learn how genetic factors interact with the environment to tip SD balance. Work focuses on zebrafish, a genetically tractable vertebrate in which environmental or genetic factors can nudge gonads to an ovary or testis fate. Zebrafish gonads develop from bipotential organs in which a few primordial germ cells (PGCs) become oocytes in all juveniles. In some individuals oocytes die and gonads become testes; in others oocytes survive and gonads become ovaries. A key question is the nature of the genetic cascade that causes oocytes to die in some juveniles and survive in others, and how environmental factors alter this cascade. Results suggest the hypothesis that the native SD locus (which we discovered in native strains but is gone from domesticated lab strains) interacts with environmental factors (likely variable nutrition and growth rates) to alter juvenile oocyte survival, which in turn changes the strength of an oocyte-derived signal acting on thegonadal soma to maintain estrogen production, thereby preserving or not preserving oocytes and gonad fate.
The aims are:
Aim 1 is to learn the molecular genetic basis of the native zebrafish SD locus.
Aim 2 is to understand the transcriptomic cascade during SD using: a) a native strain genotyped for genetic sex, b) an environmentally sensitive lab strain that lacks the native SD gene, and c) fish lacking PGCs to identify PGC- derived factors and their downstream targets.
Aim 3 is to understand mechanisms of gonadal soma/germ cell reciprocal signaling by learning the roles of the related TGFss signalers Gdf9, Amh, and Gsdf (gonadal soma derived factor), and to discover how the female-specifying signals Wnt4 and Foxl2 act in gonadal development by using induced mutations, many of which we have in hand. Innovation of proposed work includes the identification and unique use of zebrafish possessing and genotyped for the native SD locus; our generally applicable RAD-sex method for identifying sex loci in different populations; the unique mutant and transgenic resources that we make available; and our focus on gonadal soma/germ cell reciprocal signaling in zebrafish sex determination. Outcomes and impact of this work are the potential for a fuller understanding of the molecular genetic nature of the vertebrate sex-balance mechanism, which will increase our appreciation of possible mechanisms underlying increases in human reproductive diseases in developed countries.

Public Health Relevance

Understanding the biological mechanisms that tip the balance of sex determination between male and female is essential to understand recent increases in human reproductive disorders, including testis dysgenesis syndrome in men and polycystic ovary syndrome in women, that likely originate from environmental factors acting on sensitive genetic factors during development in the womb. Investigations of vertebrate species with finely balanced sex determination mechanisms may provide insight into factors that alter the sex determination balance in humans. Although many features of zebrafish gonad development are similar to those in humans, zebrafish sex determination is more labile; furthermore, genetic tools are available in zebrafish to dissect the mechanisms of sex determination, which should identify new genes and new gene functions relevant for human reproductive health.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Development - 2 Study Section (DEV2)
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Hoodbhoy, Tanya
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University of Oregon
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