Effects of constitutively active K-Ras on axon regeneration after optic nerve injury

Naoki Kiyota; Kazuhiko Namekata; Euido Nishijima; Xiaoli Guo; Atsuko Kimura; Chikako Harada; Toru Nakazawa; Takayuki Harada

doi:10.1016/j.neulet.2023.137124

Effects of constitutively active K-Ras on axon regeneration after optic nerve injury

Neurosci Lett. 2023 Mar 16:799:137124. doi: 10.1016/j.neulet.2023.137124. Epub 2023 Feb 11.

Authors

Naoki Kiyota¹, Kazuhiko Namekata², Euido Nishijima³, Xiaoli Guo³, Atsuko Kimura³, Chikako Harada³, Toru Nakazawa⁴, Takayuki Harada³

Affiliations

¹ Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; Department of Ophthalmology, Tohoku University Graduate School of Medicine, Sendai, Japan.
² Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan. Electronic address: namekata-kz@igakuken.or.jp.
³ Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
⁴ Department of Ophthalmology, Tohoku University Graduate School of Medicine, Sendai, Japan.

PMID: 36780941
DOI: 10.1016/j.neulet.2023.137124

Abstract

Visual disturbance after optic nerve injury is a serious problem. Attempts have been made to enhance the intrinsic ability of retinal ganglion cells (RGCs) to regenerate their axons, and the importance of PI3K/Akt and RAF/MEK/ERK signal activation has been suggested. Since these signals are shared with oncogenic signaling cascades, in this study, we focused on a constitutively active form of K-Ras, K-Ras^V12, to determine if overexpression of this molecule could stimulate axon regeneration. We confirmed that K-Ras^V12 phosphorylated Akt and ERK in vitro. Intravitreal delivery of AAV2-K-Ras^V12 increased the number of surviving RGCs and promoted 1.0 mm of axon regeneration one week after optic nerve injury without inducing abnormal proliferative effects in the RGCs. In addition, AAV2-K-Ras^V12 induced robust RGC axon regeneration, reaching as far as approximately 2.5 mm from the injury site, in eight weeks. Our findings suggest that AAV2-K-Ras^V12 could provide a good model for speedy and efficient analysis of the mechanism underlying axon regeneration in vivo.

Keywords: Axon regeneration; K-Ras; Neuroprotection; Optic nerve injury; Retinal ganglion cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Axons / physiology
Humans
Nerve Regeneration / physiology
Optic Nerve Injuries*
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt

Substances

Proto-Oncogene Proteins c-akt
Phosphatidylinositol 3-Kinases