The Histone Methyltransferase G9a Controls Axon Growth by Targeting the RhoA Signaling Pathway

Abstract

Highlights d G9a expression and nuclear enrichment occur early in polarizing neurons d G9a is required for neuronal migration and axon formation d G9a inhibits RhoA/ROCK activity during neuronal polarization d G9a targets Lfc, a GEF for RhoA that impairs axon growth

Fine-Tuning the TGFβ Signaling Pathway by SARA During Neuronal Development

“…However, cortical neurons replaced these neurites after axon specification to develop a bipolar morphology able to migrate toward the pial surface (Ehlers and Polleux, 2010;Kawauchi, 2015). Then, when radial migration takes place, most of the neurons located at SVZ-IZ layers exhibit a bipolar morphology, which is required for proper cortical migration (Kriegstein and Noctor, 2004;Hatanaka and Yamauchi, 2013;Mestres et al, 2016;Wilson et al, 2020). Embryonic brains expressing SARA-F728A presented a higher number of neurons with bipolar phenotype, as well as an increase in the number of neurons reaching the upper layers of the cortex, suggesting an enhancement of cortical migration (Figure 4).…”

New insights on epigenetic mechanisms supporting axonal development: histone marks and miRNAs

“…All rights reserved (GAPs) and microtubule associated proteins (MAPs) [24][25][26][27][28]. By contrast, RhoA-ROCK or GSK3β-dependent signaling pathways act as negative regulators, restraining axon elongation and preventing the formation of multiple axons [18,22,24,[29][30][31][32][33][34][35]. Together, positive and negative forces precisely control axonal extension.…”

“…In cultured hippocampal neurons, the suppression of G9a impaired polarity acquisition, with the majority of neurons failing to generate an axon, and a small percentage displaying short axons lacking a proximo-distal tau-1 gradient, a hallmark of growing axons [18]. In situ G9a knockdown blocks neuronal migration and polarization in the embryonic cortex of mouse brains; G9a-suppressed neurons failed to develop leading and trailing neurites [18]. Mechanistically, the removal of H3K9me2, by suppressing G9a, enhances the expression of Lfc.…”

“…Mechanistically, the removal of H3K9me2, by suppressing G9a, enhances the expression of Lfc. Lfc is a GEF that specifically activates RhoA, a negative regulator of axon growth and actin dynamics [18].…”

“…In situ, morphological polarization becomes evident when neurons reach the intermediate zone (IZ) of the brain cortex, displaying leading and trailing neurites (primary dendrite and axon, respectively), characteristic of the so-called bipolar stage [6,12,18,20] ( Figure 1B). In this setting, specification is defined by physical interactions between bipolar and multipolar cells in the lower IZ of the brain cortex.…”