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

J. Martin Collinson (Lead / Corresponding author), 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

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)
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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. Thepmamutation 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 ofLimk1by 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
Article numberdev160093
Pages (from-to)1-15
Number of pages15
Issue number3
Early online date8 Feb 2018
Publication statusPublished - Feb 2018


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

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology


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