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Sci Rep. 2019 Apr 1;9(1):5446. doi: 10.1038/s41598-019-41940-5.

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

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Divison of Molecular Medicine, Leeds Institute of Medical Research, University of Leeds, LS9 7TF, Leeds, UK.
Division of Human Genetics, Cincinnati Children's Hospital, 3333 Burnet Avenue, Cincinnati, OH, 45229-3039, USA.
Department of Zoology, Faculty of Science, Benha University, Benha, Egypt.
Human Development and Health, Faculty of Medicine, University of Southampton, SO16 6YD, Southampton, UK.
Divison of Molecular Medicine, Leeds Institute of Medical Research, University of Leeds, LS9 7TF, Leeds, UK.


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 Tmem67tm1(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.

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