Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Sep;150(6):709-722.
doi: 10.1111/jnc.14833. Epub 2019 Aug 26.

Inhibition of Notch1 signaling promotes neuronal differentiation and improves functional recovery in spinal cord injury through suppressing the activation of Ras homolog family member A

Zhiming Peng  1 , Xiang Li  1 , Mengxia Fu  2 , Kai Zhu  1 , Lingli Long  3 , Xiaoyang Zhao  1 , Qingui Chen  4 , David Y B Deng  5 , Yong Wan  1
Affiliations
Free article

Inhibition of Notch1 signaling promotes neuronal differentiation and improves functional recovery in spinal cord injury through suppressing the activation of Ras homolog family member A

Zhiming Peng et al. J Neurochem. 2019 Sep.
Free article

Abstract

Neural stem cells (NSCs) transplantation represents a promising strategy for the repair of injured neurons, since NSCs not only produce multiple neurotrophic growth factors but also differentiate into mature cells to replace damaged cells. Previous studies have shown that Notch signaling pathway had negative effects on neuronal differentiation; however, the precise mechanism remained inadequately understood. This research aimed to investigate whether inhibition of Notch1 signaling promotes neuronal differentiation and improves functional recovery in rat spinal cord injury through suppressing the activation of Ras homolog family member A (RhoA). QPCR, western blot, and immunofluorescence experiments were used to analyze Notch1 signaling pathways, RhoA, Ras homologous -associated coiled-coil containing protein kinase 1 (ROCK1), cleaved caspased-3, and neuronal/astrocytic differentiation markers. The expression of RhoA and ROCK1 was inhibited by lentivirus or specific biochemical inhibitors. In spinal cord injury (SCI), motor function was assessed by hind limbs movements and electrophysiology. Tissue repairing was measured by immunofluorescence, Nissl staining, Fluorogold, HE staining, QPCR, western blot, and magnetic resonance imaging (MRI) experiments. Our results demonstrate that inhibition of Notch1 in NSCs can promote the differentiation of NSCs to neurons. Knockdown of RhoA and inhibition of ROCK1 both can promote neuronal differentiation through inhibiting the activation of Notch1 signaling pathway in NSCs. In SCI, silencing RhoA enhanced neuronal differentiation and improved tissue repairing/functional recovery by inhibiting the activation of Notch1 signaling pathway. Since Notch1 inhibits neuronal differentiation through activating the RhoA/ROCK1 signaling pathway in NSCs, our data suggest that the Notch1/RhoA/ROCK1/Hes1/Hes5 signaling pathway may serve as a novel target for the treatment of SCI.

Keywords: Notch1; RhoA/ROCK1; neural stem cells; neuronal differentiation; spinal cord injury.

PubMed Disclaimer

References

    1. Artavanis-Tsakonas S., Rand M. D. and Lake R. J. (1999) Notch signaling: cell fate control and signal integration in development. Science 284, 770-776.
    1. Assinck P., Duncan G. J., Hilton B. J., Plemel J. R. and Tetzlaff W. (2017) Cell transplantation therapy for spinal cord injury. Nat. Neurosci. 20, 637-647.
    1. Basso D. M., Beattie M. S. and Bresnahan J. C. (1995) A sensitive and reliable locomotor rating scale for open field testing in rats. J. Neurotrauma 12, 1-21.
    1. Chen B. Y., Zheng M. H., Chen Y., et al. (2015) Myeloid-specific blockade of notch signaling by RBP-J knockout attenuates spinal cord injury accompanied by compromised inflammation response in mice. Mol. Neurobiol. 52, 1378-1390.
    1. Chen N., Cen J. S., Wang J., et al. (2016) Targeted inhibition of leucine-rich repeat and immunoglobulin domain-containing protein 1 in transplanted neural stem cells promotes neuronal differentiation and functional recovery in rats subjected to spinal cord injury. Crit. Care Med. 44, e146-157.

Publication types

MeSH terms

LinkOut - more resources