Transcriptional control of motor pool formation and motor circuit connectivity by the LIM-HD protein Isl2

The fidelity of motor control requires the precise positional arrangement of motor pools and the establishment of synaptic connections between these pools. In the developing spinal cord, motor nerves project to specific target muscles and receive proprioceptive input from the muscles via the sensorimotor circuit. LIM-homeodomain transcription factors are known to successively restrict specific motor neuronal fates during neural development; however, it remains unclear to what extent they contribute to limb-based motor pools and locomotor circuits. Here, we showed in mice that deletion of Isl2 resulted in scattered motor pools, primarily in the median motor column and lateral LMC (LMCl) populations, and lacked Pea3 expression in the hindlimb motor pools, accompanied by reduced terminal axon branching and disorganized neuromuscular junctions. Transcriptomic analysis of Isl2 - deficient spinal cords revealed that a variety of genes involved in motor neuron differentiation, axon development, and synapse organization were downregulated in hindlimb motor pools. Moreover, the loss of Isl2 impaired sensorimotor connectivity and hindlimb locomotion. Together, our studies indicate that Isl2 plays a critical role in organizing motor pool position and sensorimotor circuits in hindlimb motor pools.