Development of corticospinal connectivity: Implications for organization of motor control circuitry as well as motor neuron disease

Summary

Date: 
March 16, 2016 - 1:00pm
Location: 
Northwest 243
About the Speaker
Name: 
Vibhu Sahni (Macklis Lab)

The corticospinal system is the principal motor system for controlling movements that require the greatest skill and flexibility. It originates with corticospinal motor neurons (CSMN) that reside in the cerebral cortex and extend axons to the brainstem and spinal cord forming the corticospinal tract (CST). CSMN degeneration in motor neuron diseases (MNDs) such as amyotrophic lateral sclerosis (ALS), as well as damage to the CST in patients of spinal cord injury, causes spasticity and paralysis. For precise and fine motor control, CSMN axons must specifically target distinct segments – from supraspinal motor control centers in the brainstem, to cervical, thoracic, and lumbar spinal cord. The molecular basis for this segmentally specific connectivity is unknown.

We investigated molecular controls over CSMN axonal segmental targeting. We isolated functionally distinct CSMN subpopulations during development – bulbar-cervical-projecting (CSMNC) and thoraco-lumbar-projecting (CSMNL) CSMN – and identified differentially expressed genes between them. Using this approach, we identified novel controls – Klhl14 and Crim1 that direct CSMN axons to appropriate spinal levels– short axon extension by CSMNC and long axon extension by CSMNL. Together, these “STOP” and “GO” controls constitute new, bi-directional mechanisms directing CSMN axonal targeting, the first for any spinal-projecting motor pathway. Our studies lay the foundation for investigating the development, regeneration, and evolution of corticospinal circuitry, and identify potentially novel mechanisms underlying vulnerability of specific CSMN subtypes in MNDs.