C-terminal domain small phosphatase 1 (CTDSP1) regulates growth factor expression and axonal regeneration in peripheral nerve tissue

Abstract Peripheral Nerve Injury (PNI) represents a major clinical and economic burden. Despite the ability of peripheral neurons to regenerate their axons after an injury, patients are often left with motor and/or sensory disability and may develop chronic pain. Successful regeneration and target o...

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Autores principales:	Noreen M. Gervasi, Alexander Dimtchev, Desraj M. Clark, Marvin Dingle, Alexander V. Pisarchik, Leon J. Nesti
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/93e7462133694abc92607b580fe0884f
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spelling	oai:doaj.org-article:93e7462133694abc92607b580fe0884f2021-12-02T16:14:02ZC-terminal domain small phosphatase 1 (CTDSP1) regulates growth factor expression and axonal regeneration in peripheral nerve tissue10.1038/s41598-021-92822-82045-2322https://doaj.org/article/93e7462133694abc92607b580fe0884f2021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-92822-8https://doaj.org/toc/2045-2322Abstract Peripheral Nerve Injury (PNI) represents a major clinical and economic burden. Despite the ability of peripheral neurons to regenerate their axons after an injury, patients are often left with motor and/or sensory disability and may develop chronic pain. Successful regeneration and target organ reinnervation require comprehensive transcriptional changes in both injured neurons and support cells located at the site of injury. The expression of most of the genes required for axon growth and guidance and for synapsis formation is repressed by a single master transcriptional regulator, the Repressor Element 1 Silencing Transcription factor (REST). Sustained increase of REST levels after injury inhibits axon regeneration and leads to chronic pain. As targeting of transcription factors is challenging, we tested whether modulation of REST activity could be achieved through knockdown of carboxy-terminal domain small phosphatase 1 (CTDSP1), the enzyme that stabilizes REST by preventing its targeting to the proteasome. To test whether knockdown of CTDSP1 promotes neurotrophic factor expression in both support cells located at the site of injury and in peripheral neurons, we transfected mesenchymal progenitor cells (MPCs), a type of support cells that are present at high concentrations at the site of injury, and dorsal root ganglion (DRG) neurons with REST or CTDSP1 specific siRNA. We quantified neurotrophic factor expression by RT-qPCR and Western blot, and brain-derived neurotrophic factor (BDNF) release in the cell culture medium by ELISA, and we measured neurite outgrowth of DRG neurons in culture. Our results show that CTDSP1 knockdown promotes neurotrophic factor expression in both DRG neurons and the support cells MPCs, and promotes DRG neuron regeneration. Therapeutics targeting CTDSP1 activity may, therefore, represent a novel epigenetic strategy to promote peripheral nerve regeneration after PNI by promoting the regenerative program repressed by injury-induced increased levels of REST in both neurons and support cells.Noreen M. GervasiAlexander DimtchevDesraj M. ClarkMarvin DingleAlexander V. PisarchikLeon J. NestiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Noreen M. Gervasi Alexander Dimtchev Desraj M. Clark Marvin Dingle Alexander V. Pisarchik Leon J. Nesti C-terminal domain small phosphatase 1 (CTDSP1) regulates growth factor expression and axonal regeneration in peripheral nerve tissue
description	Abstract Peripheral Nerve Injury (PNI) represents a major clinical and economic burden. Despite the ability of peripheral neurons to regenerate their axons after an injury, patients are often left with motor and/or sensory disability and may develop chronic pain. Successful regeneration and target organ reinnervation require comprehensive transcriptional changes in both injured neurons and support cells located at the site of injury. The expression of most of the genes required for axon growth and guidance and for synapsis formation is repressed by a single master transcriptional regulator, the Repressor Element 1 Silencing Transcription factor (REST). Sustained increase of REST levels after injury inhibits axon regeneration and leads to chronic pain. As targeting of transcription factors is challenging, we tested whether modulation of REST activity could be achieved through knockdown of carboxy-terminal domain small phosphatase 1 (CTDSP1), the enzyme that stabilizes REST by preventing its targeting to the proteasome. To test whether knockdown of CTDSP1 promotes neurotrophic factor expression in both support cells located at the site of injury and in peripheral neurons, we transfected mesenchymal progenitor cells (MPCs), a type of support cells that are present at high concentrations at the site of injury, and dorsal root ganglion (DRG) neurons with REST or CTDSP1 specific siRNA. We quantified neurotrophic factor expression by RT-qPCR and Western blot, and brain-derived neurotrophic factor (BDNF) release in the cell culture medium by ELISA, and we measured neurite outgrowth of DRG neurons in culture. Our results show that CTDSP1 knockdown promotes neurotrophic factor expression in both DRG neurons and the support cells MPCs, and promotes DRG neuron regeneration. Therapeutics targeting CTDSP1 activity may, therefore, represent a novel epigenetic strategy to promote peripheral nerve regeneration after PNI by promoting the regenerative program repressed by injury-induced increased levels of REST in both neurons and support cells.
format	article
author	Noreen M. Gervasi Alexander Dimtchev Desraj M. Clark Marvin Dingle Alexander V. Pisarchik Leon J. Nesti
author_facet	Noreen M. Gervasi Alexander Dimtchev Desraj M. Clark Marvin Dingle Alexander V. Pisarchik Leon J. Nesti
author_sort	Noreen M. Gervasi
title	C-terminal domain small phosphatase 1 (CTDSP1) regulates growth factor expression and axonal regeneration in peripheral nerve tissue
title_short	C-terminal domain small phosphatase 1 (CTDSP1) regulates growth factor expression and axonal regeneration in peripheral nerve tissue
title_full	C-terminal domain small phosphatase 1 (CTDSP1) regulates growth factor expression and axonal regeneration in peripheral nerve tissue
title_fullStr	C-terminal domain small phosphatase 1 (CTDSP1) regulates growth factor expression and axonal regeneration in peripheral nerve tissue
title_full_unstemmed	C-terminal domain small phosphatase 1 (CTDSP1) regulates growth factor expression and axonal regeneration in peripheral nerve tissue
title_sort	c-terminal domain small phosphatase 1 (ctdsp1) regulates growth factor expression and axonal regeneration in peripheral nerve tissue
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/93e7462133694abc92607b580fe0884f
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C-terminal domain small phosphatase 1 (CTDSP1) regulates growth factor expression and axonal regeneration in peripheral nerve tissue

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