Title

The developmental and genetic basis of ‘clubfoot’ in the peroneal muscular atrophy mutant mouse

Authors

J. Martin Collinson, University of Aberdeen
Nils Lindström, University of Aberdeen
Carlos Neves, University of Aberdeen
Karen Wallace, University of Aberdeen
Caroline Meharg, University of Aberdeen
Rebecca Charles, University of Aberdeen
Zoe Ross, University of Aberdeen
Amy Fraser, University of Aberdeen
Ivan Mbogo, University of Aberdeen
Kadri Oras, University of Aberdeen
Masaru Nakamoto, Valparaiso UniversityFollow
Simon Barker, Royal Aberdeen Children's Hospital
Suzanne Duce, University of Dundee
Zosia Miedzybrodzka, University of Aberdeen
Neil Vargesson, University of Aberdeen

Document Type

Article

Publication Date

January 2018

Journal Title

Development

Issue

dev160093

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.

Recommended Citation

Collinson, J. Martin; Lindström, Nils; Neves, Carlos; Wallace, Karen; Meharg, Caroline; Charles, Rebecca; Ross, Zoe; Fraser, Amy; Mbogo, Ivan; Oras, Kadri; Nakamoto, Masaru; Barker, Simon; Duce, Suzanne; Miedzybrodzka, Zosia; and Vargesson, Neil, "The developmental and genetic basis of ‘clubfoot’ in the peroneal muscular atrophy mutant mouse" (2018). Biology Faculty Publications. 38.
https://scholar.valpo.edu/bio_fac_pub/38