Overexpression of Shrm4 promotes proliferation and differentiation of neural stem cells through activation of GABA signaling pathway

Shrm4 contributes to autophagy inhibition and neuroprotection following ischemic stroke by mediating GABA B receptor activation

“…Next, we proceeded to probe the mechanistic action underlying the effect of Shrm4 in ischemic stroke, which uncovered that Shrm4 could interact with GABA B receptor expression on the neuronal membrane. In line with this finding, a recent work revealed that Shrm4 could bind to GABA, and its overexpression or activation of GABA promoted cell viability, colony formation rate and differentiation of neural stem cells 22 . GABA B is a metabotropic transmembrane receptor, and its activation leads to opening of potassium channels and reduction in the frequency of action potentials, thus inhibiting neurotransmitter release 23 .…”

“…In line with this finding, a recent work revealed that Shrm4 could bind to GABA, and its overexpression or activation of GABA promoted cell viability, colony formation rate and differentiation of neural stem cells. 22 GABA B is a metabotropic transmembrane receptor, and its activation leads to opening of potassium channels and reduction in the frequency of action potentials, thus inhibiting neurotransmitter release. 23 The present findings revealed that baclofen (GABA B agonist) restricted neuronal autophagy and death in neurons exposed to OGD.…”

Are SHROOM4 loss‐of‐function variants pathogenic?

“…Sequencing of large cohorts of individuals with ID identified additional cases with SHROOM4 variants, including a nonsense variant (p.Gln1258*) in a male proband but also in his unaffected brothers (Redin et al, 2014), and a maternally inherited missense variant (p.Arg146Trp) in a male with Rett‐like phenotype (Lopes et al, 2016). The role of SHROOM4 in synaptogenesis and GABA signaling were proposed to support the pathogenicity of SHROOM4 in ID (Tian et al, 2020; Zapata et al, 2017). However, systematic reassessment of 106 genes proposed to be involved in monogenic forms of X‐linked ID highlighted several genes including SHROOM4 for which conclusive evidence of pathogenicity was lacking and thus, replication studies were warranted (Piton et al, 2013).…”

Neural stem cells-from quiescence to differentiation and potential clinical uses

“…While GABA acts predominantly as an inhibitor of proliferation and inductor of quiescence, glutamate stimulates cell cycle progression (Moss and Toni, 2013;Yeh et al, 2018). On the other hand, Shrm4 activates GABA B1 signaling that further leads to upregulation of anti-apoptotic and mitogen proteins' expression, along with downregulation of pro-apoptotic ones (Tian et al, 2020). Glutamate exercises its proliferative effects on NSCs and neural progenitors by increasing levels of VEGF and cyclin D1 (Liu et al, 2015), along with αamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation and calcium uptake (Song et al, 2017).…”