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Spina bifida-predisposing heterozygous mutations in Planar Cell Polarity genes and Zic2 reduce bone mass in young mice

Spina bifida-predisposing heterozygous mutations in Planar Cell Polarity genes and Zic2 reduce bone mass in young mice
Spina bifida-predisposing heterozygous mutations in Planar Cell Polarity genes and Zic2 reduce bone mass in young mice

Fractures are a common comorbidity in children with the neural tube defect (NTD) spina bifida. Mutations in the Wnt/planar cell polarity (PCP) pathway contribute to NTDs in humans and mice, but whether this pathway independently determines bone mass is poorly understood. Here, we first confirmed that core Wnt/PCP components are expressed in osteoblasts and osteoclasts in vitro. In vivo, we performed detailed μCT comparisons of bone structure in tibiae from young male mice heterozygous for NTD-associated mutations versus WT littermates. PCP signalling disruption caused by Vangl2 (Vangl2 Lp/+ ) or Celsr1 (Celsr1 Crsh/+ ) mutations significantly reduced trabecular bone mass and distal tibial cortical thickness. NTD-associated mutations in non-PCP transcription factors were also investigated. Pax3 mutation (Pax3 Sp2H/+ ) had minimal effects on bone mass. Zic2 mutation (Zic2 Ku/+ ) significantly altered the position of the tibia/fibula junction and diminished cortical bone in the proximal tibia. Beyond these genes, we bioinformatically documented the known extent of shared genetic networks between NTDs and bone properties. 46 genes involved in neural tube closure are annotated with bone-related ontologies. These findings document shared genetic networks between spina bifida risk and bone structure, including PCP components and Zic2. Genetic variants which predispose to spina bifida may therefore independently diminish bone mass.

2045-2322
Orriss, Isabel R.
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Lanham, Stuart
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Savery, Dawn
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Greene, Nicholas D.E.
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Stanier, Philip
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Oreffo, Richard
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Copp, Andrew J.
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Galea, Gabriel L.
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Orriss, Isabel R.
9071f515-7a7b-4cdc-abc3-6376177121c5
Lanham, Stuart
28fdbbef-e3b6-4fdf-bd0f-4968eeb614d6
Savery, Dawn
9142e105-392a-4be1-9f09-c37114821cb2
Greene, Nicholas D.E.
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Stanier, Philip
20df9ad5-7153-4e45-98f7-b265e15980c7
Oreffo, Richard
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Copp, Andrew J.
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Galea, Gabriel L.
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Orriss, Isabel R., Lanham, Stuart, Savery, Dawn, Greene, Nicholas D.E., Stanier, Philip, Oreffo, Richard, Copp, Andrew J. and Galea, Gabriel L. (2018) Spina bifida-predisposing heterozygous mutations in Planar Cell Polarity genes and Zic2 reduce bone mass in young mice. Scientific Reports, 8 (1), [3325]. (doi:10.1038/s41598-018-21718-x).

Record type: Article

Abstract

Fractures are a common comorbidity in children with the neural tube defect (NTD) spina bifida. Mutations in the Wnt/planar cell polarity (PCP) pathway contribute to NTDs in humans and mice, but whether this pathway independently determines bone mass is poorly understood. Here, we first confirmed that core Wnt/PCP components are expressed in osteoblasts and osteoclasts in vitro. In vivo, we performed detailed μCT comparisons of bone structure in tibiae from young male mice heterozygous for NTD-associated mutations versus WT littermates. PCP signalling disruption caused by Vangl2 (Vangl2 Lp/+ ) or Celsr1 (Celsr1 Crsh/+ ) mutations significantly reduced trabecular bone mass and distal tibial cortical thickness. NTD-associated mutations in non-PCP transcription factors were also investigated. Pax3 mutation (Pax3 Sp2H/+ ) had minimal effects on bone mass. Zic2 mutation (Zic2 Ku/+ ) significantly altered the position of the tibia/fibula junction and diminished cortical bone in the proximal tibia. Beyond these genes, we bioinformatically documented the known extent of shared genetic networks between NTDs and bone properties. 46 genes involved in neural tube closure are annotated with bone-related ontologies. These findings document shared genetic networks between spina bifida risk and bone structure, including PCP components and Zic2. Genetic variants which predispose to spina bifida may therefore independently diminish bone mass.

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Accepted/In Press date: 7 February 2018
e-pub ahead of print date: 20 February 2018
Published date: 1 December 2018

Identifiers

Local EPrints ID: 418384
URI: http://eprints.soton.ac.uk/id/eprint/418384
ISSN: 2045-2322
PURE UUID: eca5332d-87dd-4985-97cd-0a46471fda8d
ORCID for Stuart Lanham: ORCID iD orcid.org/0000-0002-4516-264X
ORCID for Richard Oreffo: ORCID iD orcid.org/0000-0001-5995-6726

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Date deposited: 06 Mar 2018 17:30
Last modified: 26 Nov 2021 02:43

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Contributors

Author: Isabel R. Orriss
Author: Stuart Lanham ORCID iD
Author: Dawn Savery
Author: Nicholas D.E. Greene
Author: Philip Stanier
Author: Richard Oreffo ORCID iD
Author: Andrew J. Copp
Author: Gabriel L. Galea

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