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Cerebellar Malformations in the Tmem67 Ciliopathy Mouse Model are Caused by Combined Wnt and Shh Signalling Systems Dysregulations
Author(s) -
Abdelhamed Zakia,
Toomes Carmel,
Inglehearn Chris,
Johnson Colin
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.lb418
Subject(s) - cerebellum , sonic hedgehog , wnt signaling pathway , ciliopathy , biology , ptch1 , gli1 , microbiology and biotechnology , hedgehog signaling pathway , homeobox , purkinje cell , phenotype , genetics , neuroscience , gene expression , gene , signal transduction
Objectives This study focuses on the characterization of the cerebellum in the newly‐described Tmem67 tm1(Dgen) knockout ciliopathy mouse model. Methods various molecular, immunohistochemical,primary neuronal cell culture methods and RNA next generation sequencing were used in this study. Results :The Tmem67 mutant cerebellar vermis was hypoplastic with foliation defects. Mutant cerebellar hemispheres had severe foliation defects and malformation of the inferior lobe, concomitant with aberrantly low canonical Wnt/β‐catenin signalling. Shh transcript levels were unaffected, but the levels of Shh signalling pathway modulators such as Ptch1 and Gli1 were significantly reduced. This resulted in reduced proliferation of granule cell precursors (GCP), with exogenous Shh stimulation failing to rescue the GCP defect. RNA sequencing and hierarchical clustering analysis identified a total 28 differentially expressed genes between Tmem67 mutant and wild type control cerebellum. Unexpectedly, a single clustered group of homeobox‐type transcription factors ( Hoxa5 , Hoxa4 , Hoxb5 and Hoxd3 ) were all significantly up‐regulated in the mutant cerebellum. Immunohistochemical analysis confirmed this finding. Conclusion Results suggest that cerebellar hypoplasia phenotype in the Tmem67 model is a combination of Wnt/β‐catenin and Shh signalling defects, causing significant changes to downstream gene expression patterns and cell‐fate specification.