Hedgehog signaling regulates Wolffian duct development through the primary cilium†

Primary cilia play pivotal roles in embryonic patterning and organogenesis through transduction of the Hedgehog signaling pathway (Hh). Although mutations in Hh morphogens impair the development of the gonads and trigger male infertility, the contribution of Hh and primary cilia in the development of male reproductive ductules, including the epididymis, remains unknown. From a Pax2(Cre); IFT88(fl/fl) knock-out mouse model, we found that primary cilia deletion is associated with imbalanced Hh signaling and morphometric changes in the Wolffian duct (WD), the embryonic precursor of the epididymis. Similar effects were observed following pharmacological blockade of primary cilia formation and Hh modulation on WD organotypic cultures. The expression of genes involved in extracellular matrix, mesenchymal-epithelial transition, canonical Hh and WD development was significantly altered after treatments. Altogether, we identified the primary cilia-dependent Hh signaling as a master regulator of genes involved in WD development. This provides new insights regarding the etiology of sexual differentiation and male infertility issues. Modulation of primary-ciliogenesis and downstream Hedgehog signaling controls Wolffian duct development.

Automated summary

Primary cilia are crucial for embryonic patterning and organogenesis through the Hedgehog signaling pathway. This study investigated the role of Hedgehog signaling and primary cilia in the development of male reproductive ductules, such as the epididymis. The findings suggest that primary cilia-dependent Hedgehog signaling acts as a master regulator of genes involved in Wolffian duct development, providing new insights into sexual differentiation and male infertility issues. Modulating primary ciliogenesis and downstream Hedgehog signaling may control the development of the Wolffian duct.