The developmental basis of clubfoot

Idiopathic clubfoot (Talipes Equinovarus) affects 1 in 500 UK births, but its aetiology is very poorly understood, with both genetic and environmental components. We investigated the developmental and genetic basis of clubfoot in a mouse model, and provide evidence that clubfoot is a neuromuscular defect. Although the tibial branch of the sciatic nerve projected to the ventral domain of the hindlimb buds, as normal during embryogenesis, the dorsal peroneal branch of the sciatic was shown by whole-mount immunostaining to display significant defects, including a failure to fasciculate, targeting errors and, in most adults, total loss of the mature peroneal nerve. This lead to wastage of dorsal calf muscles which appeared to underlie retarded rotation of the foot during development. In contrast, the developing hindlimb vasculature was unaffected. Dorso-ventral patterning of the neural tube was found to be normal in the clubfoot mouse, and patterning of the lateral motor columns was investigated by immunohistochemistry. In summary, the ankle and tarsal deformities seen in the mouse model of clubfoot are secondary to muscle atrophy following misspecification of the peroneal branch of the sciatic nerve. This aetiology, and the underlying genetic mutation, offers a new understanding of the abnormalities and causes of human clubfoot.