Desert hedgehog (Dhh) Gene Is Required in the Mouse Testis for Formation of Adult-Type Leydig Cells and Normal Development of Peritubular Cells and Seminiferous Tubules

Abstract

Testes from adult and prepubertal mice lacking the Desert hedgehog (DHH:) gene were examined in order to describe further the role of Dhh in spermatogenesis because, in a previous report, DHH:-null male mice were shown to be sterile. Dhh is a signaling molecule expressed by Sertoli cells. Its receptor, patched (Ptc), has been previously localized to Leydig cells and is herein described as being localized also to peritubular cells. Two phenotypes of the mice were observed: masculinized (7.5% of DHH:-null males) and feminized (92.5%), both of which displayed abnormal peritubular tissue and severely restricted spermatogenesis. Testes from adult feminized animals lacked adult-type Leydig cells and displayed numerous undifferentiated fibroblastic cells in the interstitium that produced abundant collagen. The basal lamina, normally present between the myoid cells and Sertoli cells, was focally absent. We speculate that the abnormal basal lamina contributed to other characteristics, such as extracordal gonocytes, apolar Sertoli cells, and anastomotic seminiferous tubules. The two DHH:-null phenotypes described have common peritubular cell defects that may be indicative of the essential role of peritubular cells in development of tubular morphology, the differentiation of Leydig cells, and the ultimate support of spermatogenesis.

Interacciones Epitelio-Mesenquimáticas en el Desarrollo Testicular

“…Se ha visto que en ratones knockout a Arx, las células intersticiales no se desarrollan (Miyabayashi et al, 2013). Existe evidencia que embriones que no expresan DHH en las células sustentaculares presentan una población reducida de células intersticiales fetales, con la consecuente producción insuficiente de andrógenos, ocasionando en el descenso testicular, atrofia genital y desarrollo de genitalia externa ambigua (Bitgood et al, 1996;Clark et al, 2000;Pierucci-Alves et al). Tras la unión al receptor PTCH1 en las células intersticiales fetales, DHH induce respuestas intracelulares por medio de factores de transcripción GLI1 y GLI2 (Szczepny et al, 2006;Sahin et al, 2014).…”

Cell‐specific ablation in the testis: what have we learned?

“…At the most basic level, knockout of Sry or Sox9 leads to sex reversal through failure of Sertoli cell specification, fundamentally demonstrating the requirement of Sertoli cells for masculinization [reviewed in (Kobayashi et al ., 2005; Wilhelm et al ., 2013)]. Within the developing testis knockout of other genes can lead to absence of specific cell types, for example knockout of PDGFR‐alpha (Brennan et al ., 2003) impacts on foetal Leydig cell development, whereas knockout of desert hedgehog (DHH) (Clark et al ., 2000), or COUPTFII (Qin et al ., 2008) leads to absence of the adult Leydig cell population; W v mutations of cKit lead to near germ‐free testes, through failure of primordial germ cell migration (De Franca et al ., 1994), whereas mutations such as the cell‐specific loss of AR from Sertoli cells leads to loss of post‐meiotic germ cells (Chang et al ., 2004; De Gendt et al ., 2004). In each of these cases, however, it is challenging to assign any downstream phenotypic impact specifically to loss of gene function or to the wider effects of cell ablation.…”

“…This work showed that Leydig cell regeneration after EDS is dependent on LH (Molenaar et al ., 1986; Sriraman et al ., 2003) although some early proliferation and differentiation appears to occur independent of LH (Teerds et al ., 1989). Subsequent studies have shown that similar control mechanisms regulate normal adult Leydig cell development at puberty (Clark et al ., 2000; Gnessi et al ., 2000; Baker & O'Shaughnessy, 2001; Zhang et al ., 2001, 2004; Baker et al ., 2003). Other factors such as DHH, PDGF and anti‐Müllerian hormone (AMH) have been implicated in the development of Leydig cells both during development and re‐generation (Salva et al ., 2004; Josso et al ., 2006; O'Shaughnessy et al ., 2008b) and further studies on EDS regeneration have also suggested that nerve growth factor (NGF) and Sertoli cells are involved in Leydig cell proliferation, differentiation and survival (Yan et al ., 2000; Zhang et al ., 2013).…”

Role of androgen and gonadotrophins in the development and function of the Sertoli cells and Leydig cells: Data from mutant and genetically modified mice

“…Unlike the fetal Leydig cell population, the factors regulating adult Leydig cell differentiation remain largely unknown. In the absence of DHH and PDGFA adult Leydig cells fail to develop but this may be related to a failure of stem cell development or proliferation (Clark et al, 2000;Gnessi et al, 2000;Park et al, 2007). It has been shown that the adult testis contains stem cells which will give rise to Leydig cells (Ge et al, 2006) but the origin of these cells and where they reside within the normal testis remains unknown.…”