Activin A, a product of fetal Leydig cells, is a unique paracrine regulator of Sertoli cell proliferation and fetal testis cord expansion

Abstract

Formation of tubular structures relies upon complex interactions between adjacent epithelium and mesenchyme. In the embryonic testes, dramatic compartmentalization leads to the formation of testis cords (epithelium) and the surrounding interstitium (mesenchyme). Sertoli cells, the epithelial cell type within testis cords, produce signaling molecules to orchestrate testis cord formation. The interstitial fetal Leydig cells, however, are thought only to masculinize the embryo and are not known to be involved in testis cord morphogenesis. Contrary to this notion, we have identified activin A, a member of the TGF-β protein superfamily, as a product of the murine fetal Leydig cells that acts directly upon Sertoli cells to promote their proliferation during late embryogenesis. Genetic disruption of activin βA, the gene encoding activin A, specifically in fetal Leydig cells resulted in a failure of fetal testis cord elongation and expansion due to decreased Sertoli cell proliferation. Conditional inactivation of Smad4 , the central component of TGF-β signaling, in Sertoli cells led to testis cord dysgenesis and proliferative defects similar to those of Leydig cell-specific activin βA knockout testes. These results indicate that activin A is the major TGF-β protein that acts directly on Sertoli cells. Testicular dysgenesis in activin βA and Smad4 conditional knockout embryos persists into adulthood, leading to low sperm production and abnormal testicular histology. Our findings challenge the paradigm that fetal testis development is solely under the control of Sertoli cells, by uncovering an active and essential role of fetal Leydig cells during testis cord morphogenesis.

Nodal/activin signaling promotes male germ cell fate and suppresses female programming in somatic cells

“…Ectopic activation of Bmp2 and follistatin might be one cause of dysgenesis of the testicular cords. Either conditional deletion of Smad4 in Sertoli cells or specific KO of the gene for activin βA in fetal Leydig cells decreased Sertoli cell proliferation and caused abnormal testicular histology (Archambeault and Yao, 2010). We therefore suggest that nodal/activin-A acts on Sertoli cells to promote cell proliferation and suppress female differentiation.…”

“…However, ectopic meiosis and the loss of NANOS2 expression in some germ cells indicates the existence of a SMAD4-dependent pathway, by which nodal/activin signaling directly regulates male germ cell fate. Moreover, if other somatic factors are triggered by nodal/activin-A that affect male germ cell fate, exclusive interruption of nodal/activin signals in somatic cells should give rise to defects in germ cells, whereas conditional deletion of Smad4 in Sertoli cells was associated with grossly normal spermatogenesis (Archambeault and Yao, 2010), implying the absence or limited function of these factors. Hence, our study presents the first evidence that nodal/activin signals act directly on germ cells.…”

“…S2A). The observations that both nodal and activin-A have the capacity to activate pSMAD2/3 signaling pathways and that pSMAD2 signals persist even in Inhba-KO testes (Archambeault and Yao, 2010;Mendis et al, 2011) Tamoxifen was injected at E10.5 and gonads were harvested at E14.5 and E16.5. The results of RT-qPCR indicated that the Nodal gene was successfully deleted using Cre recombinase (Fig.…”

Interacciones Epitelio-Mesenquimáticas en el Desarrollo Testicular

“…La diferenciación de las célu-las intersticiales (de Leydig) es regulada por el morfógeno Desert Hedgehog (DHH), secretado por las células sustentaculares (Pierucci-Alves et al, 2001), aunque también están involucrados el factor de crecimiento derivado de plaquetas (PDGFA) y el gen Homeobox Arx (Griswold & Behringer). A su vez, las células intersticiales fetales poseen receptores Patched1 (PTCH1) para DHH y PDGFRA para PDGFA, y responden produciendo activina A, el cual actúa como un regulador paracrino de la proliferación de los sustentocitos y de la expansión del cordón testicular (Archambeault & Yao, 2010).…”

Adult testicular dysgenesis of Inhba conditional knockout mice may also be caused by disruption of cross-talk between Leydig cells and germ cells

“…In a recent article, Archambeault and Yao (1) reported that genetic disruption of activin A resulted in a failure of fetal testiscord elongation and expansion because of decreased Sertoli cell proliferation. They uncovered a role of fetal Leydig cells during testis-cord morphogenesis through activin A signaling pathway.…”