WDR11‐mediated Hedgehog signalling defects underlie a new ciliopathy related to Kallmann syndrome

Abstract

WDR11 has been implicated in congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS), human developmental genetic disorders defined by delayed puberty and infertility. However, WDR11's role in development is poorly understood. Here, we report that WDR11 modulates the Hedgehog (Hh) signalling pathway and is essential for ciliogenesis. Disruption of WDR11 expression in mouse and zebrafish results in phenotypic characteristics associated with defective Hh signalling, accompanied by dysgenesis of ciliated tissues. Wdr11‐null mice also exhibit early‐onset obesity. We find that WDR11 shuttles from the cilium to the nucleus in response to Hh signalling. WDR11 regulates the proteolytic processing of GLI3 and cooperates with the transcription factor EMX1 in the induction of downstream Hh pathway gene expression and gonadotrophin‐releasing hormone production. The CHH/KS‐associated human mutations result in loss of function of WDR11. Treatment with the Hh agonist purmorphamine partially rescues the WDR11 haploinsufficiency phenotypes. Our study reveals a novel class of ciliopathy caused by WDR11 mutations and suggests that CHH/KS may be a part of the human ciliopathy spectrum.

Endosome-to-TGN Trafficking: Organelle-Vesicle and Organelle-Organelle Interactions

“…Intriguingly, mutations of WDR11 have been found in patients with congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS), developmental disorders characterized by delayed puberty and infertility . WDR11 is essential for normal ciliogenesis, by being involved in the Hedgehog (Hh) signaling pathway (Kim et al, 2018). However, it is unclear whether TBC1D23 is also involved in these processes.…”

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

“…WDR11 belongs to a family of proteins with the evolutionarily conserved WD40-repeat (WDR) domains, forming βpropeller structures known to mediate protein-protein interactions (7;11). Our previous studies of a Wdr11 knockout (KO) mouse model have indicated a critical role for WDR11 in development (12). Wdr11 is required for normal ciliogenesis as loss of Wdr11 resulted in short and infrequent primary cilia.…”

“…Wdr11 is required for normal ciliogenesis as loss of Wdr11 resulted in short and infrequent primary cilia. Since multiple developmental signalling pathways functionally rely on primary cilia, the majority of Wdr11 KO embryos die in utero at midgestation (after E12.5) with severe developmental defects (12). Those rare individual mice that survived through adulthood display features overlapping with KS/CHH such as delayed puberty and infertility, accompanied by reduced levels of GnRH and gonadotrophins.…”

“…In addition, Wdr11 KO mice are born with hypoplastic gonads containing fewer germ cells compared to the wild type (WT) littermates. Wdr11-deficient testes are smaller in size and contain fewer spermatocytes and spermatids with an increased frequency of morphologically abnormal sperm found in the seminiferous tubules (12). Wdr11-deficient ovaries are also smaller than WT and present with disproportionally higher numbers of oogonia or primordial follicles and reduced numbers of mature follicles (12).…”

High-Resolution Episcopic Microscopy (HREM): Looking Back on 13 Years of Successful Generation of Digital Volume Data of Organic Material for 3D Visualisation and 3D Display

“…DMDD independent stand-alone studies researching genetic regulation of mouse development include the analysis of: normal and abnormal cardiovascular development [49][50][51][52][53][54][55][56][57][58][59][60][61]; the development of the limbs, cloaca and pancreas [42,[62][63][64]; ciliopathies [65]; and the characterisation of cardiac defects in Down syndrome mouse models [66,67]. Despite its value for analysing such processes in embryos between embryonic day E8.5 and E14.5, when organogenesis is already finished, HREM also proved its value for analysing developmental processes in very early embryos immediately after implantation [68].…”