Journal
JOURNAL OF NEUROSCIENCE
Volume 41, Issue 50, Pages 10247-10260Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2649-20.2021
Keywords
corticospinal neuron; motor cortex; Pten; regeneration; RhoA; spinal cord injury
Categories
Funding
- NationalInstitute of Neurological Disorders and Stroke [NS100772, NS115963, NS119508, NS093002]
- Craig Neilsen Foundation
- New Jersey Commission of Spinal Cord Research
- Precursory Research for Embryonic Science and Technology (Japan Science and Technology Agency) [JPMJPR13M8]
- Japan Agency for Medical Research and Development Core Research for Evolutionary Science and Technology (AMED-CREST) [JP21gm1210005]
- Moonshot Research [J21zf0127004]
- Japan Society for the Promotion of Science (JSPS) [17H04985, 17H05556, 17K19443, 21H02590, 21H05683]
- JSPS
- KANAE Foundation for the Promotion of Medical Science
- Kato Memorial Bioscience Foundation
- Tokyo Biochemical Research Foundation
- Narishige Neuroscience Research Foundation
- Ube Industries Foundation
- Takeda Science Foundation
- Japan Heart Foundation Research Grant
- GeneralInsurance Association of Japan
- Center for Neuroanatomy with NeurotropicViruses (NationalInstitutes of Health Grant) [P40RR018604]
- Grants-in-Aid for Scientific Research [21H02590, 21H05683, 17H04985, 17K19443, 17H05556] Funding Source: KAKEN
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Deleting RhoA and RhoC genes to eliminate extrinsic inhibitory pathways, as well as deleting the PTEN gene to enhance intrinsic regenerative response, were found to promote neural circuit rewiring through a combinatorial approach. While this method increased the potential for rewiring, it did not significantly impact axon regrowth across the lesion and motor recovery.
Axon regeneration after spinal cord injury (SCI) is limited by both a decreased intrinsic ability of neurons to grow axons and the growth-hindering effects of extrinsic inhibitory molecules expressed around the lesion. Deletion of phosphatase and tensin homolog (Pten) augments mechanistic target of rapamycin (mTOR) signaling and enhances the intrinsic regenerative response of injured corti-cospinal neurons after SCI. Because of the variety of growth-restrictive extrinsic molecules, it remains unclear how inhibition of con-served inhibitory signaling elements would affect axon regeneration and rewiring after SCI. Moreover, it remains unknown how a combinatorial approach to modulate both extrinsic and intrinsic mechanisms can enhance regeneration and rewiring after SCI. In the present study, we deleted RhoA and RhoC, which encode small GTPases that mediate growth inhibition signals of a variety of extrin-sic molecules, to remove global extrinsic pathways. RhoA/RhoC double deletion in mice suppressed retraction or dieback of corticospi-nal axons after SCI. In contrast, Pten deletion increased regrowth of corticospinal axons into the lesion core. Although deletion of both RhoA and Pten did not promote axon regrowth across the lesion or motor recovery, it additively promoted rewiring of cortico-spinal circuits connecting the cerebral cortex, spinal cord, and hindlimb muscles. Our genetic findings, therefore, reveal that a combi-natorial approach to modulate both intrinsic and extrinsic factors can additively promote neural circuit rewiring after SCI.
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