![]() Single-cell RNA sequencing (scRNAseq) approaches affords the sensitivity to identify transcriptional heterogeneity among CSNs. 8, 9 Pro-axon growth candidates Lppr1 and Inpp5k were identified via retrograde labeling of sprouting CSNs in the cervical spinal cord, suggesting that retro-labeling of plastic CSNs from the lumbar would identify a separate set of factors. Recent data from our laboratory supports differential sensitivity of CSN subdivisions, as we showed that novel pro-plasticity factors identified in intact CSNs undergoing functional plasticity after unilateral pyramidotomy stimulate growth of lesioned and intact forelimb CST axons, while having no effects on lumbar projecting CSNs. Despite clear anatomical subdivisions of the CST, i.e., CSNs with terminals in the thalamus, brainstem, and cervical and lumbar spinal cord, in vitro, and in vivo screening approaches designed to identify novel axon growth activators overlook molecular heterogeneity within these neurons and thus dilute the most potent candidates among differentially sensitive subtypes of cells. 7– 9 The inefficacy of these interventions is partially due to an incomplete understanding of the molecular heterogeneity among CSNs. 4– 6 While strides have been made in stimulating axotomized CSNs to regenerate or intact CSNs to undergo plasticity after injury, recovery of motor function remains woefully incomplete. Efforts to repair the damaged CST have broadly focused on either nullifying the effects of the axon growth inhibitory environment of the mature CNS, or recapitulating cell autonomous developmental mechanisms to re-build the damaged tract. 2, 3 The complex wiring of the mature CST, together with its central role in voluntary and fine motor control means that damage leads to significant and lasting functional impairments. The CST is wired postnatally, and after exuberant developmental terminal arborization in spinal grey matter, is pruned via activity-dependent mechanisms during a protracted critical period that ultimately sculpts a mature motor pathway. 1 Corticospinal neurons (CSNs) in layer Vb of sensorimotor cortex project their axons through the internal capsule which then decussate in the brainstem and innervate every spinal segment along the neuroaxis, where they synapse on spinal interneurons whose axons activate motor neurons to initiate and refine movement. The corticospinal tract (CST) is the major descending motor pathway responsible for fine coordinated movement in mammals. Our results provide molecular insight into the differences between anatomically distinct CSN subtypes and provide a resource for future screening and exploitation of these subtypes to repair the damaged CST after injury and disease. These markers are expressed in embryonic and neonatal CSNs and can be used to study early postnatal patterning of the CST. By leveraging retrograde tracing, we are able to compare forelimb and hindlimb projecting CSNs, identifying subtype-specific markers, including Cacng7 and Slc16a2 respectively. By comparing CSNs to non-spinally projecting neurons in layer Vb, we identify pan-CSN markers including Wnt7b. In this study, we combine retrograde CST tracing with single-cell RNA sequencing to build a comprehensive atlas of CSN subtypes. ![]() These repair strategies are sub-optimal in part due to underexplored molecular heterogeneity within the developing and adult CST. While novel pro-axon growth activators have stimulated plasticity and regeneration of corticospinal neurons (CSNs) after injury, robust functional recovery remains elusive. The corticospinal tract (CST) is refractory to repair after CNS trauma, resulting in chronic debilitating functional motor deficits after spinal cord injury.
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