Development of the embryonic gonad is the first critical step in determining the reproductive functionality of the adult individual. Sexual ambiguity, infertility, or neoplasia arises when defects occur in early gonad development. The main goal of this proposal is to understand the fundamental process of gonad development, especially as regards the development of the ovary. Development of the mammalian ovary is considered as a default pathway, arising only in the absence of Sry-directed testis pathway. However, our recent findings revealed that the development of the ovary is a product of an active signaling cascade, involving complex cell-cell interaction and cell fate determination. We have identified two novel molecules, WNT4 and follistatin, that play critical roles during early ovary development. Wnt4 and follistatin null mice had identical defects in embryonic ovaries including formation of a testis-specific vasculature and loss of germ cells. Furthermore, we found that follistatin is the direct downstream effector of WNT4 to regulate the vasculature and germ cell development. We therefore hypothesize that WNT4 and follistatin are constituents of a novel signaling cascade to inhibit testis-specific vasculature and to maintain the survival of female germ cells in ovary development. We propose three specific aims to: 1) dissect the intracellular signaling pathways of WNT4;2) understand the regulation and functions of follistatin in ovary development;and 3) establish the functional relationship between formation of the testis specific vasculature and germ cell loss in follistatin null gonads. By combining transgenic and organ culture techniques, we expect to decipher the molecular and cellular pathways for the development of the ovary and at the same time, identify the critical components susceptible to genetic defects in these pathways.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD046861-05
Application #
7534810
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Taymans, Susan
Project Start
2005-01-01
Project End
2010-11-30
Budget Start
2008-12-01
Budget End
2010-11-30
Support Year
5
Fiscal Year
2009
Total Cost
$312,500
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Archambeault, Denise R; Yao, Humphrey Hung-Chang (2014) Loss of smad4 in Sertoli and Leydig cells leads to testicular dysgenesis and hemorrhagic tumor formation in mice. Biol Reprod 90:62
Liu, Chang; Paczkowski, Melissa; Othman, Manal et al. (2012) Investigating the origins of somatic cell populations in the perinatal mouse ovaries using genetic lineage tracing and immunohistochemistry. Methods Mol Biol 825:211-21
Archambeault, Denise R; Tomaszewski, Jessica; Childs, Andrew J et al. (2011) Testicular somatic cells, not gonocytes, are the major source of functional activin A during testis morphogenesis. Endocrinology 152:4358-67
Barsoum, Ivraym; Yao, Humphrey H C (2011) Redundant and differential roles of transcription factors Gli1 and Gli2 in the development of mouse fetal Leydig cells. Biol Reprod 84:894-9
Liu, Chia-Feng; Parker, Keith; Yao, Humphrey H-C (2010) WNT4/beta-catenin pathway maintains female germ cell survival by inhibiting activin betaB in the mouse fetal ovary. PLoS One 5:e10382
Gupta, Rupesh K; Singh, Jeffery M; Leslie, Tracie C et al. (2010) Di-(2-ethylhexyl) phthalate and mono-(2-ethylhexyl) phthalate inhibit growth and reduce estradiol levels of antral follicles in vitro. Toxicol Appl Pharmacol 242:224-30
Liu, Chia-Feng; Liu, Chang; Yao, Humphrey H-C (2010) Building pathways for ovary organogenesis in the mouse embryo. Curr Top Dev Biol 90:263-90
Huang, Chen-Che J; Yao, Humphrey H C (2010) Inactivation of Dicer1 in Steroidogenic factor 1-positive cells reveals tissue-specific requirement for Dicer1 in adrenal, testis, and ovary. BMC Dev Biol 10:66
Archambeault, Denise R; Yao, Humphrey Hung-Chang (2010) Activin A, a product of fetal Leydig cells, is a unique paracrine regulator of Sertoli cell proliferation and fetal testis cord expansion. Proc Natl Acad Sci U S A 107:10526-31
Huang, Chen-Che Jeff; Miyagawa, Shinichi; Matsumaru, Daisuke et al. (2010) Progenitor cell expansion and organ size of mouse adrenal is regulated by sonic hedgehog. Endocrinology 151:1119-28

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