Itoh Y, Sahni V, Shnider SJ, McKee H, Macklis JD. 2023. Inter-axonal molecular crosstalk via Lumican proteoglycan sculpts murine cervical corticospinal innervation by distinct subpopulations. Cell reports. 42(3):112182. Pubmed: 36934325 DOI:S2211-1247(23)00193-6


How CNS circuits sculpt their axonal arbors into spatially and functionally organized domains is not well understood. Segmental specificity of corticospinal connectivity is an exemplar for such regional specificity of many axon projections. Corticospinal neurons (CSN) innervate spinal and brainstem targets with segmental precision, controlling voluntary movement. Multiple molecularly distinct CSN subpopulations innervate the cervical cord for evolutionarily enhanced precision of forelimb movement. Evolutionarily newer CSN exclusively innervate bulbar-cervical targets, while CSN are heterogeneous; distinct subpopulations extend axons to either bulbar-cervical or thoraco-lumbar segments. We identify that Lumican controls balance of cervical innervation between CSN and CSN axons during development, which is maintained into maturity. Lumican, an extracellular proteoglycan expressed by CSN, non-cell-autonomously suppresses cervical collateralization by multiple CSN subpopulations. This inter-axonal molecular crosstalk between CSN subpopulations controls murine corticospinal circuitry refinement and forelimb dexterity. Such crosstalk is generalizable beyond the corticospinal system for evolutionary incorporation of new neuron populations into preexisting circuitry.
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

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Jeffrey Macklis investigates molecular controls and mechanisms over neuron subtype specification, development, diversity, axon guidance-circuit formation, and pathology in the cerebral cortex. His lab seeks to apply developmental controls toward brain and spinal cord regeneration and directed differentiation for in vitro mechanistic modeling using human assembloids.

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