Axon Fasciculation, Mediated by Transmembrane Semaphorins, Is Critical for the Establishment of Segmental Specificity of Corticospinal Circuits.

Autor:	Gu Z; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229., Matsuura K; Neural Circuit Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, 904-0495, Japan., Letelier A; Burke Neurological Institute, White Plains, New York 10605., Basista M; Burke Neurological Institute, White Plains, New York 10605.; Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10065., Craig C; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229., Imai F; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229.; Burke Neurological Institute, White Plains, New York 10605.; Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10065., Yoshida Y; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 yoy4001@med.cornell.edu.; Burke Neurological Institute, White Plains, New York 10605.; Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10065.; Neural Circuit Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, 904-0495, Japan.
Jazyk:	angličtina
Zdroj:	The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2023 Aug 09; Vol. 43 (32), pp. 5753-5768. Date of Electronic Publication: 2023 Jun 21.
DOI:	10.1523/JNEUROSCI.0073-22.2023
Abstrakt:	Axon fasciculation is thought to be a critical step in neural circuit formation and function. Recent studies have revealed various molecular mechanisms that underlie axon fasciculation; however, the impacts of axon fasciculation, and its corollary, defasciculation, on neural circuit wiring remain unclear. Corticospinal (CS) neurons in the sensorimotor cortex project axons to the spinal cord to control skilled movements. In rodents, the axons remain tightly fasciculated in the brain and traverse the dorsal funiculus of the spinal cord. Here we show that plexinA1 (PlexA1) and plexinA3 (PlexA3) receptors are expressed by CS neurons, whereas their ligands, semaphorin-5A (Sema5A) and semaphorin-5B (Sema5B) are expressed in the medulla at the decussation site of CS axons to inhibit premature defasciculation of these axons. In the absence of Sema5A/5B-PlexA1/A3 signaling, some CS axons are prematurely defasciculated in the medulla of the brainstem, and those defasciculated CS axons aberrantly transverse in the spinal gray matter instead of the spinal dorsal funiculus. In the absence of Sema5A/Sema5B-PlexA1/A3 signaling, CS axons, which would normally innervate the lumbar spinal cord, are unbundled in the spinal gray matter, and prematurely innervate the cervical gray matter with reduced innervation of the lumbar gray matter. In both Sema5A/5B and PlexA1/A3 mutant mice (both sexes), stimulation of the hindlimb motor cortex aberrantly evokes robust forelimb muscle activation. Finally, Sema5A/5B and PlexA1/A3 mutant mice show deficits in skilled movements. These results suggest that proper fasciculation of CS axons is required for appropriate neural circuit wiring and ultimately affect the ability to perform skilled movements. SIGNIFICANCE STATEMENT Axon fasciculation is believed to be essential for neural circuit formation and function. However, whether and how defects in axon fasciculation affect the formation and function of neural circuits remain unclear. Here we examine whether the transmembrane proteins semaphorin-5A (Sema5A) and semaphorin-5B (Sema5B), and their receptors, plexinA1 (PlexA1) and plexinA3 (PlexA3) play roles in the development of corticospinal circuits. We find that Sema5A/Sema5B and PlexA1/A3 are required for proper axon fasciculation of corticospinal neurons. Furthermore, Sema5A/5B and PlexA1/A3 mutant mice show marked deficits in skilled motor behaviors. Therefore, these results strongly suggest that proper corticospinal axon fasciculation is required for the appropriate formation and functioning of corticospinal circuits in mice. (Copyright © 2023 the authors.)
Databáze:	MEDLINE
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