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Primary cilia defects result in a group of related pleiotropic malformation syndromes known as ciliopathies, often characterised by cerebellar developmental and foliation defects. Here, we describe the cerebellar anatomical and signalling defects in the  Tmem67   tm1 ( Dgen )/ H   knockout mouse. At mid-gestation,  Tmem67  mutant cerebella were hypoplastic and had aberrantly high canonical Wnt/β-catenin signalling, proliferation and apoptosis. Later in development, mutant cerebellar hemispheres had severe foliation defects and inferior lobe malformation, characterized by immature Purkinje cells (PCs). Early postnatal  Tmem67  mutant cerebellum had disrupted ciliogenesis and reduced responsiveness to Shh signalling. Transcriptome profiling of  Tmem67  mutant cerebella identified ectopic increased expression of homeobox-type transcription factors ( Hoxa5 ,  Hoxa4 ,  Hoxb5  and  Hoxd3 ), normally required for early rostral hindbrain patterning. HOXB5 protein levels were increased in the inferior lobe, and increased canonical Wnt signalling, following loss of TMEM67, was dependent on HOXB5. HOXB5 occupancy at the β-catenin promoter was significantly increased by activation of canonical Wnt signalling in  Tmem67  −/−  mutant cerebellar neurones, suggesting that increased canonical Wnt signalling following mutation or loss of TMEM67 was directly dependent on HOXB5. Our results link dysregulated expression of Hox group genes with ciliary Wnt signalling defects in the developing cerebellum, providing new mechanistic insights into ciliopathy cerebellar hypoplasia phenotypes.

The ciliary Frizzled-like receptor Tmem67 regulates canonical Wnt/β-catenin signalling in the developing cerebellum via Hoxb5