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

The ciliary frizzled like receptor Tmem67 regulates canonical Wnt/β-catenin signalling in the developing cerebellum via Hoxb5
The ciliary frizzled like receptor Tmem67 regulates canonical Wnt/β-catenin signalling in the developing cerebellum via Hoxb5
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 Tmem67tm1Dgen/H1 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.
2045-2322
Abdelhamed, Zakia
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Abdelmottableb, Dina I.
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El-Asrag, Mohammed
c698d7f9-8dc8-4256-bfb2-759c1b9a7c5b
Natarajan, Subaashini
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Wheway, Gabrielle
2e547e5d-b921-4243-a071-2208fd4cc090
Inglehearn, Chris F.
2ea446cd-ae05-4382-ab37-b7fd8ffe0f46
Toomes, Carmel
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Johnson, Colin A.
e1e0b3b7-c016-4a1a-a1e4-cb86ce740db8
Abdelhamed, Zakia
cb5a6d4c-deae-4f64-837c-179ced752f33
Abdelmottableb, Dina I.
2bce63c9-5e2c-4a11-b838-f3787dc8f146
El-Asrag, Mohammed
c698d7f9-8dc8-4256-bfb2-759c1b9a7c5b
Natarajan, Subaashini
6d704e1d-3e93-48ee-9e09-6fcda5e3108f
Wheway, Gabrielle
2e547e5d-b921-4243-a071-2208fd4cc090
Inglehearn, Chris F.
2ea446cd-ae05-4382-ab37-b7fd8ffe0f46
Toomes, Carmel
7c1e8471-3578-459c-b08a-3836e5485b5c
Johnson, Colin A.
e1e0b3b7-c016-4a1a-a1e4-cb86ce740db8

Abdelhamed, Zakia, Abdelmottableb, Dina I., El-Asrag, Mohammed, Natarajan, Subaashini, Wheway, Gabrielle, Inglehearn, Chris F., Toomes, Carmel and Johnson, Colin A. (2019) The ciliary frizzled like receptor Tmem67 regulates canonical Wnt/β-catenin signalling in the developing cerebellum via Hoxb5. Scientific Reports. (doi:10.1038/s41598-019-41940-5).

Record type: Article

Abstract

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 Tmem67tm1Dgen/H1 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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Abdelhamed et al 2018 Tmem67 cerebellum 14 Mar 2019 - Accepted Manuscript
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Accepted/In Press date: 15 March 2019
e-pub ahead of print date: 1 April 2019

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Local EPrints ID: 429638
URI: https://eprints.soton.ac.uk/id/eprint/429638
ISSN: 2045-2322
PURE UUID: 4291c333-7f8f-4115-8a5e-0605ca399651
ORCID for Gabrielle Wheway: ORCID iD orcid.org/0000-0002-0494-0783

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Date deposited: 02 Apr 2019 16:30
Last modified: 03 Apr 2019 00:21

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Contributors

Author: Zakia Abdelhamed
Author: Dina I. Abdelmottableb
Author: Mohammed El-Asrag
Author: Subaashini Natarajan
Author: Chris F. Inglehearn
Author: Carmel Toomes
Author: Colin A. Johnson

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