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

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 mutation was mapped and a candidate gene encoding LIM-domain kinase 1 () 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 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.

A Community Audit of 300 “Drop-Out” Instances in Children Undergoing Ponseti Clubfoot Care in Bangladesh—What Do the Parents Say?

“…The low relapse rates detected in the children who had dropped-out from treatment in this community audit is perhaps surprising (just 9%; 21% in our previous longer-term study [8]), and reinforces the fact that clubfoot is a non-homogenous condition [31][32][33].…”

Minoxidil decreases collagen I deposition and tissue-like contraction in clubfoot-derived cells: a way to improve conservative treatment of relapsed clubfoot?

“…Two knockout mouse models of clubfoot were recently established. 44,45 Further research is necessary in order to achieve the desired sustainable antifibrotic effect in vivo, probably with MXD bound to a biomacromolecular carrier with affinity to the affected tissue. Such a targeted carrier can increase the efficacy of the treatment, can simultaneously reduce possible side-effects, and can lessen the immunogenicity of the drug (for a review, see 46 ).…”

The Cofilin/Limk1 Pathway Controls the Growth Rate of Both Developing and Regenerating Motor Axons

“…Disrupting the process of temporal axon guidance results in axons being at the wrong place at a particular developmental time. Upregulating Limk1 in MNs results in defects in motor axon growth and pathfinding, which mimic the human clubfoot phenotype (Collinson et al, 2018). In contrast, downregulating Limk1 activity results in commissural axons reaching the floor plate too early (Phan et al, 2010) and precocious motor axon growth (this study).…”