Loss of Kallmann syndrome-associated gene WDR11 disrupts primordial germ cell development by affecting canonical and non-canonical Hedgehog signalling

Abstract

Mutations of WDR11 are associated with Kallmann syndrome (KS) and congenital hypogonadotrophic hypogonadism (CHH), typically caused by defective functions of gonadotrophin-releasing hormone (GnRH) neurones in the brain. We previously reported that Wdr11 knockout mice show profound infertility with significantly fewer germ cells present in the gonads. To understand the underlying mechanisms mediated by WDR11 in these processes, we investigated the effects of Wdr11 deletion on primordial germ cell (PGC) development. Using live-tracking of PGCs and primary co-cultures of genital ridges (GR), we demonstrated that Wdr11-deficient embryos contained reduced numbers of PGCs which had delayed migration due to significantly decreased proliferation and motility. We found primary cilia-dependent canonical Hedgehog (Hh) signalling was required for proliferation of the somatic mesenchymal cells of GR, while primary cilia-independent non-canonical Hh signalling mediated by Ptch2/Gas1 and downstream effectors Src and Creb was required for PGC proliferation and migration, which was disrupted by the loss of function mutations of WDR11. Therefore, canonical and non-canonical Hh signalling are differentially involved in the development of somatic and germ cell components of the gonads, and WDR11 is required for both of these pathways operating in parallel in GR and PGCs, respectively, during normal PGC development. Our study provides a mechanistic link between the development of GnRH neurones and germ cells mediated by WDR11, which may underlie some cases of KS/CHH and ciliopathies.