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

• Published in: EMBO reports Vol. 19; no. 2; pp. 269 - 289
• Main Authors: Kim, Yeon‐Joo, Osborn, Daniel PS, Lee, Ji‐Young, Araki, Masatake, Araki, Kimi, Mohun, Timothy, Känsäkoski, Johanna, Brandstack, Nina, Kim, Hyun‐Taek, Miralles, Francesc, Kim, Cheol‐Hee, Brown, Nigel A, Kim, Hyung‐Goo, Martinez‐Barbera, Juan Pedro, Ataliotis, Paris, Raivio, Taneli, Layman, Lawrence C, Kim, Soo‐Hyun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2018; Blackwell Publishing Ltd; John Wiley and Sons Inc
• Subjects: Age; Animals; Biopsy; Cilia; Ciliopathies - genetics; Ciliopathies - metabolism; ciliopathy; Congenital diseases; Cytoplasm; Disorders; EMBO05; EMBO24; EMBO37; Gene Expression; Gene Expression Profiling; Gene Knockout Techniques; Genetic Association Studies; Genetic disorders; Genotype; Gli3 protein; Haploinsufficiency; Hedgehog protein; Hedgehog Proteins - metabolism; hedgehog signal pathway; Humans; Hypogonadism; hypogonadotropic hypogonadism; Infertility; kallmann syndrome; Kallmann Syndrome - diagnosis; Kallmann Syndrome - genetics; Kallmann Syndrome - metabolism; Kallmann's syndrome; Magnetic Resonance Imaging; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; Mutation; Nuclei; Organ Specificity - genetics; Patched-1 Receptor - genetics; Phenotype; Pituitary (anterior); Promoter Regions, Genetic; Protein Binding; Protein Transport; Proteolysis; Puberty; Signal Transduction; Signaling; Transcriptome; WDR11; Zebrafish; kallmann syndrome; hypogonadotropic hypogonadism; hedgehog signal pathway; ciliopathy; WDR11
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.201744632

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. Synopsis WDR11, the causative gene for congenital hypogonadotrophic hypogonadism and Kallmann syndrome, promotes Hedgehog singaling and ciliogenesis, linking these diseases to the human ciliopathy spectrum. WDR11 functions as a novel element of the Hedgehog (Hh) signal pathway, which regulates fundamental aspects of mammalian development. WDR11 shuttles between the nucleus and cytoplasm in response to Hh‐signaling. WDR11 is required for the processing of GLI3 protein, forms a tertiary complex with EMX1 and GLI3 and regulates the expression of novel target genes EMX1/2 and GNRH1. WDR11 is a cilia‐associated protein suggesting that CHH/KS with WDR11 mutations are ciliopathy disorders. Graphical Abstract WDR11, the causative gene for congenital hypogonadotrophic hypogonadism and Kallmann syndrome, promotes Hedgehog singaling and ciliogenesis, linking these diseases to the human ciliopathy spectrum.