Defects in non-canonical Wnt signalling and actin cytoskeleton remodelling as pathogenic mechanisms in Meckel–Gruber syndrome

Abstract

Primary cilia are mechano- and chemosensory organelles that have a fundamental role in regulating embryogenesis. Inherited disorders that involve aberrant ciliary structure or function are now known as “ciliopathies”, and they invariably present with cystic kidney dysplasia. Meckel–Gruber syndrome (MKS) is a pleiotropic ciliopathy characterized by severe defects in neurodevelopment that include occipital encephalocele, hydrocephaly and severe neural tube defects. Several MKS genes are now known, including MKS1 and MKS3/TMEM67, encoding the proteins MKS1 and meckelin, a novel receptor. Remarkably, MKS is allelic and overlaps in phenotype with the neurodevelopmental disorder Joubert syndrome (JS), with some of the causative genes implicated in regulation of the Hedgehog signalling pathway. However, our recent work has suggested a role for meckelin and some other MKS proteins in modulating non-canonical Wnt signalling and remodelling the actin cytoskeleton. Meckelin is localized at the apical cell surface, basal bodies and ciliary axoneme of ciliated cell lines and tissues, but also interacts with other MKS proteins and the actin-binding proteins nesprin-2 and filamin A. Loss of expression of MKS genes following RNAi-mediated knockdown or in MKS patient fibroblasts: (1) prevents the movement of the basal body to the apical cell surface prior to ciliogenesis; (2) causes hyperactivation of the small GTPase RhoA and Dishevelled, both implicated in the control of apical docking of basal bodies and planar polarization of epithelial cells; and (3) remodels the actin cytoskeleton. These findings are reiterated in the Mks3/Tmem67 knock-out mouse model of MKS/JS. In contrast, MKS1 is implicated in constraining canonical Wnt signalling. These findings therefore underline the critical role of MKS proteins in ciliogenesis and regulation of Wnt signalling, through interactions with apical cell surface proteins associated with the actin cytoskeleton and implicated in basal body docking.