Osterixfunctions downstream of anti-Müllerian hormone signaling to regulate Müllerian duct regression

Abstract

In mammals, the developing reproductive tract primordium of male and female fetuses consists of the Wolffian duct and the Müllerian duct (MD), two epithelial tube pairs surrounded by mesenchyme. During male development, mesenchyme-epithelia interactions mediate MD regression to prevent its development into a uterus, oviduct, and upper vagina. It is well established that transforming growth factor-β family member anti-Müllerian hormone (AMH) secreted from the fetal testis and its type 1 and 2 receptors expressed in MD mesenchyme regulate MD regression. However, little is known about the molecular network regulating downstream actions of AMH signaling. To identify potential AMH-induced genes and regulatory networks controlling MD regression in a global nonbiased manner, we examined transcriptome differences in MD mesenchyme between males (AMH signaling on) and females (AMH signaling off) by RNA-seq analysis of purified fetal MD mesenchymal cells. This analysis found 82 genes up-regulated in males during MD regression and identified ()/, a key transcriptional regulator of osteoblast differentiation and bone formation, as a downstream effector of AMH signaling during MD regression. /OSX was expressed in a male-specific pattern in MD mesenchyme during MD regression. OSX expression was lost in mutant males without AMH signaling. In addition, transgenic mice ectopically expressing human AMH in females induced a male pattern of expression. Together, these results indicate that AMH signaling is necessary and sufficient for expression in the MD mesenchyme. In addition, MD regression was delayed in-null males, identifying as a factor that regulates MD regression.

Single-cell sequencing of neonatal uterus reveals an Misr2+ endometrial progenitor indispensable for fertility

“…For consistency and clarity, we will refer to these persistent Misr2+ subluminal mesenchymal cells in the MIS-treated animal as ‘inhibited progenitors’, although this function remains presumptive. In response to MIS, these inhibited putative progenitors expressed high levels of Smad6 , a negative regulator of TGFβ signaling, and a previously reported canonical downstream target of MIS in the Mullerian mesenchyme (Figure 2E), suggesting MIS signaling was both operational and autonomous to these Misr2 + cells (Clarke et al, 2001; Mullen et al, 2018).…”

“…Supporting this interpretation of recapitulated mesenchymal regression is the ectopic expression of many of the same genes and pathways previously identified in the regressing male fetal Mullerian duct ( Bambi, Smad6, Wif1, etc .) (Mullen et al, 2018).…”

Transcriptional landscape of the embryonic chicken Müllerian duct

“…The datasets reveal novel genes and developmental pathways that are activated during duct formation, providing a rich source of genetic data for further research into the molecular control duct morphogenesis. One previous study carried out RNA-seq on the mesenchymal compartment of mouse Müllerian duct specifically during the phase of duct regression in male embryos [ 50 ]. The aim of that study was to identify genes and pathways engaged by AMH during the regression process.…”

A gene regulatory network for Müllerian duct regression

“…A transcriptome analysis of RNA-seq data generated from purified E14.5 male and female Müllerian duct mesenchyme identified Osterix ( Osx ), also known as Sp7 , as a male-enriched gene [42]. Osx was originally identified as a gene required for osteoblast differentiation [43].…”

“…Osx is expressed in a sexually dimorphic manner in the Müllerian duct mesenchyme. At E14.5, Osx expression is detected in the Müllerian ducts of male fetuses, whereas no expression was detected in the Müllerian ducts of female fetuses [42]. This male-specific expression continues throughout the remaining regression process [42].…”