Clubfoot is a common developmental abnormality of the hindlimb that causes inward and downward rotation of the foot. The condition has a strong genetic component, but the identity of the main genes involved, and indeed the aetiology of clubfoot during limb development, have remained unclear. Now, Martin Collinson and colleagues report a developmental and genetic analysis of the ‘peroneal muscular atrophy’ (PMA) mouse mutant, a model for clubfoot. Loss of the peroneal nerve in PMA mutants is preceded by the sciatic nerve's failure to properly enter the hindlimb and project to the lower muscle blocks, and failure of innervation precedes muscular atrophy. Neuronal patterning and proliferation are normal in early developmental stages, but axons show reduced growth ex vivo, suggesting an autonomous defect in axon growth. The authors identify a pma candidate gene, Limk1, which shows increased expression at the time at which hindlimb innervation fails. Furthermore, Limk1 overexpression in the chick disrupts innervation and leads to clubfoot-like phenotypes. Pharmacological inhibition of actin turnover disrupts the peroneal nerve, and genetic interaction studies support a pathway involving EphA4, Limk1, cofilin and actin in the pma phenotype. This paper provides developmental, genetic and molecular insight into the aetiology of clubfoot, and provides a platform for further mechanistic studies.
Clubfoot: Limk1 hits a nerve
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Clubfoot: Limk1 hits a nerve. Development 1 February 2018; 145 (3): e0303. doi:
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