Kim, Y-J;
Osborn, DP;
Lee, J-Y;
Araki, M;
Araki, K;
Mohun, T;
Känsäkoski, J;
... Kim, S-H; + view all
(2018)
WDR11-mediated Hedgehog signalling defects underlie a new ciliopathy related to Kallmann syndrome.
EMBO Reports
, 19
(2)
pp. 269-289.
10.15252/embr.201744632.
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WDR11-mediated Hedgehog signalling defects underlie a new ciliopathy related to Kallmann syndrome.pdf - Published Version Download (3MB) | Preview |
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.
| Type: | Article |
|---|---|
| Title: | WDR11-mediated Hedgehog signalling defects underlie a new ciliopathy related to Kallmann syndrome |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.15252/embr.201744632 |
| Publisher version: | http://dx.doi.org/10.15252/embr.201744632 |
| Language: | English |
| Additional information: | Copyright © 2017 The Authors. This is an open access article under the terms of the Creative Commons Attribution 4.0 License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | WDR11, ciliopathy, hedgehog signal pathway, hypogonadotropic hypogonadism, kallmann syndrome |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10039326 |
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