The activin a pathway in fetal testis development and dysgenesis in the mouse

Although initially identified as an “activator” of follicle-stimulating hormone release from the pituitary, activin A can also function as a paracrine factor in many tissue contexts. As a member of the transforming growth factor β (TGFβ) superfamily, activin A can elicit changes in target cell proliferation, differentiation, and function via the SMAD signaling pathway. Inhibin βA (Inhba), the gene encoding activin A, is expressed within the interstitial compartment of murine and human fetal testes; however, the role of Inhba/activin A during testis morphogenesis is unknown. To investigate whether Inhba is required for testis development in the mouse, I analyzed fetal testis morphogenesis in Inhba-/- mice. In the absence of Inhba expression, I observed significant reductions in Sertoli cell proliferation leading to impairment of testis cord elongation and coiling. Using a conditional knockout approach, I was able to pinpoint the murine fetal Leydig cells as the primary source of interstitial Inhba/activin A. To identify the cellular targets of fetal Leydig cell-derived activin A, I produced mouse models lacking expression of Smad4, a central component of TGFβ superfamily signaling, in specific cell types within the testis. Deletion of Smad4 from the Sertoli cell epithelium recapitulated the fetal testis cord dysgenesis present in Inhba-/- mice, indicating the Sertoli cells are likely the direct targets of activin A signaling. I have thus identified a novel mesenchymal-epithelial crosstalk in the developing testes wherein interstitial fetal Leydig cells produce activin A that acts upon the Sertoli cell epithelium to promote proliferation. This testicular activin A pathway is critical for elongation and convolution of the testis cords during late embryogenesis. Furthermore, I have uncovered the first evidence of an active role for fetal Leydig cells during testis cord development. Fetal testis cord dysgenesis resulting from disrupted testicular activin A signaling persists into adulthood, confirming the importance of this signaling pathway in laying the groundwork for normal testicular development and function during postnatal life.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

VMS - Veterinary Biosciences

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2010

Author dc:creator

• Archambeault, Denise R.

Contributors dc:contributor

• Yao, Humphrey H-C.
• Flaws, Jodi A.
• Nowak, Romana A.
• Bunick, David
• Jorgensen, Joan S.

• activin
• bisphenol A
• endocrine disruptor
• epithelial/mesenchymal interaction
• mouse
• Smad
• testis cords
• testis
• testicular dysgenesis
• transforming growth factor beta

Statement dc:rights

• Copyright 2010 Denise R. Archambeault

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/16019

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/16019