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

J. Martin Collinson*, Nils O. Lindström, Carlos Neves, Karen Wallace, Caroline Meharg, Rebecca H. Charles, Zoe K. Ross, Amy M. Fraser, Ivan Mbogo, Kadri Oras, Masaru Nakamoto, Simon Barker, Suzanne Duce, Zosia Miedzybrodzka, Neil Vargesson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


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.

Original languageEnglish (US)
Article numberdev160093
JournalDevelopment (Cambridge)
Issue number3
StatePublished - Feb 2018


  • Axon guidance
  • Chicken
  • Clubfoot
  • Limb development
  • Limk1

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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