PgmNr Z6106: Polycystic ovarian syndrome in zebrafish mutants for the TGF-beta signaling molecule Gsdf.

Authors:
J. Postlethwait 1 ; Y.-L. Yan 1 ; T. Desvignes 1 ; R. BreMiller 1 ; C. Wilson 1 ; M. Kossack 2 ; B. Draper 2


Institutes
1) Univ Oregon, Eugene, OR; 2) Univ of California, Davis, CA.


Abstract:

In gonad development, somatic cells support germ cell development, and reciprocally, germ cells help sustain the development and function of somatic gonad support cells. Currently we lack a full understanding of mechanisms and molecules that perform these functions. To learn about gonad ó soma signaling, we used TALENs to knock out gsdf (gonadal soma derived factor), which encodes a ray-fin fish-specific TGF-beta signaling molecule. Gsdf is the major sex determinant in the Luzon medaka, but whether it performs this role in zebrafish is unknown. Several deletion alleles were isolated and all shown to produce similar female sterile phenotypes. Results showed that in wild types, gonadal expression of gsdf starts in the somatic cells surrounding the primary germ cells in indifferent gonads before 12 days post fertilization and continues into adulthood in granulosa cells in ovaries and Sertoli cells in testes. Mutant ovaries and testes both showed substantial down-regulation of gsdf transcript. Mutant ovaries never developed follicles beyond stage III and did not sequester yolk protein, and instead accumulated thousands of early stage oocytes, leading to sterility. Gene expression studies showed that ovarian follicle cells were abnormal in mutants and failed to express cyp19a1a (aromatase), amh (antiMüllerian hormone) and gata4 normally. Mutant testes were also enlarged, but males were fertile. Mutant testes had normal expression levels of sox9a but elevated expression of amh. Zebrafish gsdf mutant females had aberrant accumulation of lipid in several organs, abnormal expression of the insulin receptor and several lipid metabolism genes. In addition, qPCR confirmed that estrogen receptor and vitellogenin were misexpressed in the livers of gsdf mutant females. Mutant ovaries down-regulated many genes involved in sex differentiation, steroid biosynthesis, hormone signaling, cell signaling, and apoptosis and proliferation. These experiments show that in zebrafish, gsdf does not have a major effect on sex determination, but rather provides a signal from the gonadal soma to the germ line that regulates oocyte maturation but not germ cell proliferation. Downstream consequences of the lack of Gsdf activity result in a phenotype that mimics human females with polycystic ovarian syndrome (PCOS), with accumulation of immature ovarian follicles, diminished expression of genes encoding steroid hormone biosynthesizing enzymes, obesity, diabetes, and female sterility, thus suggesting a role of TGF-beta signaling molecules in the etiology of PCOS.



ZFIN Genetics Index
1. gsdf