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Olig2-Induced Semaphorin Expression Drives Corticospinal Axon Retraction After Spinal Cord Injury.

ABSTRACT: Axon regeneration is limited in the central nervous system, which hinders the reconstruction of functional circuits following spinal cord injury (SCI). Although various extrinsic molecules to repel axons following SCI have been identified, the role of semaphorins, a major class of axon guidance molecules, has not been thoroughly explored. Here we show that expression of semaphorins, including Sema5a and Sema6d, is elevated after SCI, and genetic deletion of either molecule or their receptors (neuropilin1 and plexinA1, respectively) suppresses axon retraction or dieback in injured corticospinal neurons. We further show that Olig2+ cells are essential for SCI-induced semaphorin expression, and that Olig2 binds to putative enhancer regions of the semaphorin genes. Finally, conditional deletion of Olig2 in the spinal cord reduces the expression of semaphorins, alleviating the axon retraction. These results demonstrate that semaphorins function as axon repellents following SCI, and reveal a novel transcriptional mechanism for controlling semaphorin levels around injured neurons to create zones hostile to axon regrowth.

SUBMITTER: Ueno M

PROVIDER: S-EPMC8179623 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Olig2-Induced Semaphorin Expression Drives Corticospinal Axon Retraction After Spinal Cord Injury.

Ueno Masaki M Nakamura Yuka Y Nakagawa Hiroshi H Niehaus Jesse K JK Maezawa Mari M Gu Zirong Z Kumanogoh Atsushi A Takebayashi Hirohide H Lu Qing Richard QR Takada Masahiko M Yoshida Yutaka Y

Cerebral cortex (New York, N.Y. : 1991) 20201001 11

Axon regeneration is limited in the central nervous system, which hinders the reconstruction of functional circuits following spinal cord injury (SCI). Although various extrinsic molecules to repel axons following SCI have been identified, the role of semaphorins, a major class of axon guidance molecules, has not been thoroughly explored. Here we show that expression of semaphorins, including Sema5a and Sema6d, is elevated after SCI, and genetic deletion of either molecule or their receptors (ne ...[more]

PMID: 32564090

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Project description:Key pointsDamage to corticospinal axons has implications for the development of spasticity following spinal cord injury (SCI). Here, we examined to what extent residual corticospinal connections and spasticity are present in muscles below the injury (quadriceps femoris and soleus) in humans with motor complete thoracic SCI. We found three distinct subgroups of people: participants with spasticity and corticospinal responses in the quadriceps femoris and soleus; participants with spasticity and corticospinal responses in the quadriceps femoris only; and participants with no spasticity or corticospinal responses in either muscle. Spasticity and corticospinal responses were present in the quadriceps but never only in the soleus muscle, suggesting a proximal to distal gradient of symptoms of hyperreflexia. These results suggest that concomitant patterns of residual corticospinal connectivity and spasticity exist in humans with motor complete SCI and that a clinical examination of spasticity might be a good predictor of residual descending motor pathways in people with severe paralysis.AbstractThe loss of corticospinal axons has implications for the development of spasticity following spinal cord injury (SCI). However, the extent to which residual corticospinal connections and spasticity are present across muscles below the injury remains unknown. To address this question, we tested spasticity using the Modified Ashworth Scale and transmission in the corticospinal pathway by examining motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation over the leg motor cortex (cortical MEPs) and by direct activation of corticospinal axons by electrical stimulation over the thoracic spine (thoracic MEPs), in the quadriceps femoris and soleus muscles, in 30 individuals with motor complete thoracic SCI. Cortical MEPs were also conditioned by thoracic electrical stimulation at intervals allowing their summation or collision. We found three distinct subgroups of participants: 47% showed spasticity in the quadriceps femoris and soleus muscles; 30% showed spasticity in the quadriceps femoris muscle only; and 23% showed no spasticity in either muscle. Although cortical MEPs were present only in the quadriceps in participants with spasticity, thoracic MEPs were present in both muscles when spasticity was present. Thoracic electrical stimulation facilitated and suppressed cortical MEPs, showing that both forms of stimulation activated similar corticospinal axons. Cortical and thoracic MEPs correlated with the degree of spasticity in both muscles. These results provide the first evidence that related patterns of residual corticospinal connectivity and spasticity exist in muscles below the injury after motor complete thoracic SCI and highlight that a clinical examination of spasticity can predict residual corticospinal connectivity after severe paralysis.

Dataset Information

Olig2-Induced Semaphorin Expression Drives Corticospinal Axon Retraction After Spinal Cord Injury.

Publications

Olig2-Induced Semaphorin Expression Drives Corticospinal Axon Retraction After Spinal Cord Injury.

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