Integrin-Driven Axon Regeneration in the Spinal Cord Activates a Distinctive CNS Regeneration Program

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378041%3A_____%2F23%3A00580785" target="_blank" >RIV/68378041:_____/23:00580785 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.jneurosci.org/content/43/26/4775" target="_blank" >https://www.jneurosci.org/content/43/26/4775</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1523/JNEUROSCI.2076-22.2023" target="_blank" >10.1523/JNEUROSCI.2076-22.2023</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Integrin-Driven Axon Regeneration in the Spinal Cord Activates a Distinctive CNS Regeneration Program

Popis výsledku v původním jazyce

The peripheral branch of sensory dorsal root ganglion (DRG) neurons regenerates readily after injury unlike their central branch in the spinal cord. However, extensive regeneration and reconnection of sensory axons in the spinal cord can be driven by the expression of a9 integrin and its activator kindlin-1 (a9k1), which enable axons to interact with tenascin-C. To elucidate the mechanisms and downstream pathways affected by activated integrin expression and central regeneration, we conducted transcriptomic analyses of adult male rat DRG sensory neurons transduced with a9k1, and controls, with and without axotomy of the central branch. Expression of a9k1 without the central axotomy led to upregulation of a known PNS regeneration program, including many genes associated with peripheral nerve regeneration. Coupling a9k1 treatment with dorsal root axotomy led to extensive central axonal regeneration. In addition to the program upregulated by a9k1 expression, regeneration in the spinal cord led to expression of a distinctive CNS regeneration program, including genes associated with ubiquitination, autophagy, endoplasmic reticulum (ER), trafficking, and signaling. Pharmacological inhibition of these processes blocked the regeneration of axons from DRGs and human iPSC-derived sensory neurons, validating their causal contributions to sensory regeneration. This CNS regeneration-associated program showed little correlation with either embryonic development or PNS regeneration programs. Potential transcriptional drivers of this CNS program coupled to regeneration include Mef2a, Runx3, E2f4, and Yy1. Signaling from integrins primes sensory neurons for regeneration, but their axon growth in the CNS is associated with an additional distinctive program that differs from that involved in PNS regeneration.

Název v anglickém jazyce

Integrin-Driven Axon Regeneration in the Spinal Cord Activates a Distinctive CNS Regeneration Program

Popis výsledku anglicky

The peripheral branch of sensory dorsal root ganglion (DRG) neurons regenerates readily after injury unlike their central branch in the spinal cord. However, extensive regeneration and reconnection of sensory axons in the spinal cord can be driven by the expression of a9 integrin and its activator kindlin-1 (a9k1), which enable axons to interact with tenascin-C. To elucidate the mechanisms and downstream pathways affected by activated integrin expression and central regeneration, we conducted transcriptomic analyses of adult male rat DRG sensory neurons transduced with a9k1, and controls, with and without axotomy of the central branch. Expression of a9k1 without the central axotomy led to upregulation of a known PNS regeneration program, including many genes associated with peripheral nerve regeneration. Coupling a9k1 treatment with dorsal root axotomy led to extensive central axonal regeneration. In addition to the program upregulated by a9k1 expression, regeneration in the spinal cord led to expression of a distinctive CNS regeneration program, including genes associated with ubiquitination, autophagy, endoplasmic reticulum (ER), trafficking, and signaling. Pharmacological inhibition of these processes blocked the regeneration of axons from DRGs and human iPSC-derived sensory neurons, validating their causal contributions to sensory regeneration. This CNS regeneration-associated program showed little correlation with either embryonic development or PNS regeneration programs. Potential transcriptional drivers of this CNS program coupled to regeneration include Mef2a, Runx3, E2f4, and Yy1. Signaling from integrins primes sensory neurons for regeneration, but their axon growth in the CNS is associated with an additional distinctive program that differs from that involved in PNS regeneration.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

<a href="/cs/project/EF15_003%2F0000419" target="_blank" >EF15_003/0000419: Centrum rekonstrukčních neurověd</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2023

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of Neuroscience

ISSN

0270-6474

e-ISSN

1529-2401

Svazek periodika

43

Číslo periodika v rámci svazku

26

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

20

Strana od-do

4775-4794

Kód UT WoS článku

001033553700003

EID výsledku v databázi Scopus

2-s2.0-85164062750