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Laboratory for Cell Fate Specification and Circuit Development
Paralysis is the leading cause of disability worldwide and curing this disability will ultimately require repairing neural circuits that control movement. Our current focus is aimed at corticospinal repair and plasticity. This neural circuit, which connects the cerebral cortex with spinal circuits, is the principal motor system responsible for voluntary movement. Damage to the corticospinal system is a principal cause of disability following stroke, spinal cord injury, cerebral palsy and motor neuron disease.
A main focus of our work is identifying the molecular program that directs corticospinal projections to specific levels of the nervous system. These projections can extend from the cortex to either the brainstem, or spinal cord at distinct spinal levels – e.g. cervical, thoracic, or lumbar cord. Projections to distinct levels are responsible for distinct movements’ e.g. cervical projections control arm movement while lumbar projections control leg movement. How these projections are established during development remains unknown. Using single cell profiling of developing corticospinal neurons, we are beginning to establish some of the earliest molecular differences between these segmentally distinct projections (Figure 1). Our hope is that these developmental genes could eventually be recruited toward directing regeneration of segmentally-specific corticospinal connectivity in instances of injury or disease.
In a separate set of experiments, we are investigating the molecular basis for decline of long-distance corticospinal axon regenerative ability during development (Figure 2). The failure of long distance regrowth of the corticospinal axons (“wires” that connect the cortex with its targets) is a principal cause for disability after spinal cord injury. Our results indicate that long-distance axon growth ability of corticospinal axons is lost at distinct segmental levels at distinct times. This intriguingly suggests that molecular mechanisms controlling development of segmentally distinct corticospinal projections (as shown in Figure 1) might also underlie corticospinal regenerative ability.