Sex and hedgehog: roles of genes in the hedgehog signaling pathway in mammalian sexual differentiation

Abstract

The chromosome status of the mammalian embryo initiates a multistage process of sexual development in which the bipotential reproductive system establishes itself as either male or female. These events are governed by intricate cell–cell and interorgan communication that is regulated by multiple signaling pathways. The hedgehog signaling pathway was originally identified for its key role in the development of Drosophila, but is now recognized as a critical developmental regulator in many species, including humans. In addition to its developmental roles, the hedgehog signaling pathway also modulates adult organ function, and misregulation of this pathway often leads to diseases, such as cancer. The hedgehog signaling pathway acts through its morphogenetic ligands that signal from ligand-producing cells to target cells over a specified distance. The target cells then respond in a graded manner based on the concentration of the ligands that they are exposed to. Through this unique mechanism of action, the hedgehog signaling pathway elicits cell fate determination, epithelial–mesenchymal interactions, and cellular homeostasis. Here, we review current findings on the roles of hedgehog signaling in the sexually dimorphic development of the reproductive organs with an emphasis on mammals and comparative evidence in other species.

A Novel <b><i>AMH</i></b> Missense Mutation in a Patient with Persistent Müllerian Duct Syndrome

“…external genitalia under influence of hormones produced by the gonads [Wilhelm et al, 2007;Franco and Yao, 2012]. Testosterone produced by testicular Leydig cells will induce the differentiation of the male reproductive tract, i.e.…”

Sex‐specific regulation of aging in Caenorhabditis elegans

“…Accumulating evidence indicates that Hh signaling plays a pivotal role in mammalian sexual differentiation (Franco & Yao, 2012) and that the mammalian Fem1b protein, an orthologue of FEM‐1, also suppresses the transcriptional activity of GLI1 (Gilder, Chen, Jackson, Jiang & Maher, 2013). In addition, Hh signaling regulates whole‐body energy metabolism via activating the Akt/FOXO pathway (Zhang, Cheng, Wang, Leung & Mak, 2017) and also influences IIS activity in certain developmental events (Lipinski et al., 2005).…”

“…A potential consensus site found in the first intronic sequence of FOXO3 showed a strong conservation across the orthologous regions of mammalian, in particular primate, genomes. In addition, accumulating evidence indicates that Hh signaling plays a fundamental role in mammalian sexual differentiation (Franco & Yao, 2012; Wang et al., 2013). Based on this evolutionary conservation and gender‐specific activity of Hh signaling, we speculate that a similar regulatory interaction between Hh signaling and FOXO‐like transcription factors may also operate in humans to determine lifespan unequally in the two genders.…”

Aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids

“…The HH pathway is important in many normal and abnormal cellular functions, including embryonic development, stem cell proliferation and cancer genesis (reviewed by Varjosalo & Taipale (2008), Choi et al (2011), Harris et al (2011) and Park et al (2011)). The HH pathway is also crucial to the development of reproductive tract (Franco & Yao 2012), uterine function (Takamoto et al 2005, Lee et al 2006a) and uterine malignancies (Feng et al 2007, Kim et al 2009). Despite evidence for a role of HH in the uterus, and our results demonstrate that the HH pathway is active in cultured myometrial and fibroid cells; NR2F2 and CTNNB1 mRNA expressions were not affected by SHH treatment.…”

“…Acting through its receptor (PR), progesterone increases uterine expression of HH protein, which in turn regulates NR2F2 expression (Lee et al 2006b, Simon et al 2009a. HH is crucial to normal and abnormal uterine (and endometrial) development and is also regulated by progesterone (Feng et al 2007, Kim et al 2009, Wei et al 2010, Franco & Yao 2012. Currently, however, data are lacking on the potential roles of progesterone, RA and/or SHH regulatory molecules in controlling CTNNB1 and/or NR2F2 in human myometrium and fibroid tissues.…”