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Development. 2018 Feb 8;145(3). pii: dev160093. doi: 10.1242/dev.160093.

The developmental and genetic basis of 'clubfoot' in the peroneal muscular atrophy mutant mouse.

Author information

1
School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK m.collinson@abdn.ac.uk.
2
School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK.
3
Royal Aberdeen Children's Hospital, Foresterhill, Aberdeen AB25 2ZN, UK.
4
School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.

Abstract

Genetic factors underlying the human limb abnormality congenital talipes equinovarus ('clubfoot') remain incompletely understood. The spontaneous autosomal recessive mouse 'peroneal muscular atrophy' mutant (PMA) is a faithful morphological model of human clubfoot. In PMA mice, the dorsal (peroneal) branches of the sciatic nerves are absent. In this study, the primary developmental defect was identified as a reduced growth of sciatic nerve lateral motor column (LMC) neurons leading to failure to project to dorsal (peroneal) lower limb muscle blocks. The pma mutation was mapped and a candidate gene encoding LIM-domain kinase 1 (Limk1) identified, which is upregulated in mutant lateral LMC motor neurons. Genetic and molecular analyses showed that the mutation acts in the EphA4-Limk1-Cfl1/cofilin-actin pathway to modulate growth cone extension/collapse. In the chicken, both experimental upregulation of Limk1 by electroporation and pharmacological inhibition of actin turnover led to defects in hindlimb spinal motor neuron growth and pathfinding, and mimicked the clubfoot phenotype. The data support a neuromuscular aetiology for clubfoot and provide a mechanistic framework to understand clubfoot in humans.

KEYWORDS:

Axon guidance; Chicken; Clubfoot; Limb development; Limk1

PMID:
29439133
PMCID:
PMC5818009
DOI:
10.1242/dev.160093
[Indexed for MEDLINE]
Free PMC Article

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