Molecular controls over corticospinal motor neuron segmental targeting

Authors: *V. V. SAHNI1, S. SHNIDER1, D. JABAUDON2, J. SONG1, F. DING1, J. D. MACKLIS1;
1Stem Cell and Regenerative Biol. and Ctr. for Brain Sci., Harvard Univ., Cambridge, MA; 2Univ. of Geneva, Geneva, Switzerland

Vibhu Sahni, Harvard University

The corticospinal system controls performance of skilled and complex movements. For precise motor control, distinct corticospinal motor neurons (CSMN) extend axons to, and innervate, distinct target spinal cord segments – from rostral targets in the brainstem and cervical cord (controlling face and forelimb movements) to caudal targets in the thoracic and lumbar cord (controlling hindlimb movements). The molecular basis for this segmentally specific connectivity is unknown.
We identified specific CSMN subpopulations that exhibit striking axon targeting specificity during development. We identified that CSMN in rostrolateral sensorimotor cortex extend axons exclusively to subcerebral targets in the brainstem and cervical spinal cord (CSMNBC), and do not extend axons past these targets toward thoracic or lumbar cord. CSMNBC largely reside outside primary motor cortex (M1), comprise a significant subset of the total cortical projections to the cervical spinal cord, and exhibit distinct spinal connectivity from CSMN in M1 in the mature CNS. In complementary fashion, CSMN extending axons past the cervical cord toward thoracic and lumbar spinal segments (CSMNTL) reside exclusively in medial sensorimotor cortex, residing entirely within M1.
We isolated CSMNBC and CSMNTL during development, and identified differentially expressed genes between them. Using this approach, we identified that:
1. CSMN subpopulations are molecularly distinct from the earliest stages of development.
2. Using transgenic Cre reporter mouse lines, we find that these molecular controls prospectively identify developing CSMN subpopulations that eventually extend axons to bulbar-cervical versus thoraco-lumbar segments.
3. Using intersectional mouse genetics, we additionally find that CSMNTL extend exuberant collaterals into cervical spinal segments. This indicates that mechanisms controlling CSMN axon targeting versus axonal collateralization to specific spinal segments are independent of one another.
4. We identify that a subset of these controls direct CSMN axons to appropriate spinal levels – bulbar-cervical extension by CSMNBC and thoraco-lumbar extension by CSMNTL. These axon extension decisions occur prior to axonal collateralization, and therefore are independent of connectivity.
Together, these newly identified controls constitute new mechanisms directing CSMN axonal targeting. This work provides foundation for further investigation of mechanisms directing the development, regeneration, and evolution of precise corticospinal circuitry, and the roles of molecularly distinct CSMN subpopulations in voluntary motor control.

Disclosures
V.V. Sahni: None. S. Shnider: None. D. Jabaudon: None. J. Song: None. F. Ding: None. J.D. Macklis: None.
LINK: Society for Neuroscience

Grant Support
ALS Association
Travis Roy Foundation
Packard Center for ALS Research
Massachusetts Dept of Public Health

Vibhu Sahni

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