Isl2 regulates motor pool organization and motor connectivity

Abstract

The intricate arrangement of motor pools and the formation of synaptic connections between them play a critical role in achieving precise motor control. During neural development, motor neurons (MNs) are topographically clustered into distinct functional subsets, called motor pools. Motor nerves innervate specific target muscles in the spinal cord and receive proprioceptive feedback from these muscles via the sensorimotor circuit. LIM-homeodomain transcription factors play a pivotal role in successively restricting distinct motor neuronal fates. Nevertheless, their precise contribution to limb-based motor pools and locomotor circuits remains unclear. This study investigates the role of Isl2, a LIM-homeodomain transcription factor, in motor pool organization. The ablation of Isl2 led to the dispersion of motor pools, predominantly affecting the median motor column (MMC) and lateral motor column (LMC) populations. Hindlimb motor pools lacked Etv4 expression, and reduced terminal axon branching and disorganized neuromuscular junctions were observed in Isl2-deficient mice. Transcriptomic analysis of spinal cords from Isl2-deficient mice revealed downregulation of various genes associated with motor neuron differentiation, axon development, synapse organization, and locomotion in hindlimb motor pools. Consequently, sensorimotor connectivity and hindlimb locomotion were impaired in Isl2-deficient mice. These findings highlight the essential role of Isl2 in orchestrating motor pool positioning and sensorimotor circuitry in hindlimb motor pools. This research sheds light on the molecular underpinnings of motor control and its potential ramifications for comprehending motor-related disorders in humans.