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

Orriss, I R; Lanham, S A; Savery, D; Greene, N D E; Stanier, P; Oreffo, R; Copp, A J; Galea, G L

doi:10.1038/s41598-018-21718-x

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

Orriss, I R; Lanham, S A; Savery, D; Greene, N D E; Stanier, P; Oreffo, R; Copp, A J; Galea, G L

Authors

I R Orriss

S A Lanham

D Savery

N D E Greene

P Stanier

R Oreffo

A J Copp

G L Galea

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 (Vangl2Lp/+) or Celsr1 (Celsr1Crsh/+) mutations significantly reduced trabecular bone mass and distal tibial cortical thickness. NTD-associated mutations in non-PCP transcription factors were also investigated. Pax3 mutation (Pax3Sp2H/+) had minimal effects on bone mass. Zic2 mutation (Zic2Ku/+) 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.

Citation

Orriss, I. R., Lanham, S. A., Savery, D., Greene, N. D. E., Stanier, P., Oreffo, R., …Galea, G. L. (in press). Spina bifida-predisposing heterozygous mutations in Planar Cell Polarity genes and Zic2 reduce bone mass in young mice. https://doi.org/10.1038/s41598-018-21718-x

Journal Article Type	Article
Acceptance Date	Feb 7, 2018
Deposit Date	Mar 9, 2018
Publicly Available Date	Mar 9, 2018
Journal	Scientific Reports (Nature)
Peer Reviewed	Peer Reviewed
Volume	8
Pages	3325
DOI	https://doi.org/10.1038/s41598-018-21718-x
Public URL	https://rvc-repository.worktribe.com/output/1388813