Defects in human limb growth and development are typically attributed to genetic and environmental factors and less commonly to the role of the nervous system. Chronic lack of neural activity, whether due to disuse, environmental factors, or, most commonly, nerve trauma, adversely affects muscle, bone, and joint development. The most prominent example of this problem is disruption of the brachial plexus during birth, a condition that can affect the entire upper limb. The dynamic interactions between motor nerve axons and skeletal muscle fibers have been well described. During late fetal and early postnatal human development, muscle tissue provides crucial trophic support to influence motor-neuron survival and differentiation. In return, motor-neuron innervation and activity provide signals that result in muscle growth and differentiation, including increased synthesis of contractile proteins, clustering of acetylcholinesterase at neuromuscular junctions, and the ultrastructural shaping of the mature neuromuscular junction. Early interactions between motor axons and muscles also prune multiple axonal inputs to each muscle fiber (polyneuronal innervation) to a one-to-one ratio between axon terminals and muscle fibers, thereby facilitating coordination between nerves and muscles. The loss of motor innervation during this critical period results in substantial loss of spinal cord motor neurons due to a lack of muscle-derived trophic support, preventing restoration of full muscle function1,2. Loss of muscle contraction during growth causes joint contractures3. Similar to motor axons, neonatal sensory neurons require trophic support (in particular, nerve growth factor) from target tissue. Interruption in the supply of this trophic support results in loss of a large proportion of neurons in the dorsal root ganglion, which inevitably restricts sensory reinnervation2. Loss of limb innervation in the fetal or perinatal period also results in reduced growth and development of bone, as evidenced by decreased size, incomplete formation of attachment …