The Stemness Gene Mex3A Is a Key Regulator of Neuroblast Proliferation During Neurogenesis

Abstract

Mex3A is an RNA binding protein that can also act as an E3 ubiquitin ligase to control gene expression at the post-transcriptional level. In intestinal adult stem cells, MEX3A is required for cell self-renewal and when overexpressed, MEX3A can contribute to support the proliferation of different cancer cell types. In a completely different context, we found mex3A among the genes expressed in neurogenic niches of the embryonic and adult fish brain and, notably, its expression was downregulated during brain aging. The role of mex3A during embryonic and adult neurogenesis in tetrapods is still unknown. Here, we showed that mex3A is expressed in the proliferative region of the developing brain in both Xenopus and mouse embryos. Using gain and loss of gene function approaches, we showed that, in Xenopus embryos, mex3A is required for neuroblast proliferation and its depletion reduced the neuroblast pool, leading to microcephaly. The tissue-specific overexpression of mex3A in the developing neural plate enhanced the expression of sox2 and msi-1 keeping neuroblasts into a proliferative state. It is now clear that the stemness property of mex3A, already demonstrated in adult intestinal stem cells and cancer cells, is a key feature of mex3a also in developing brain, opening new lines of investigation to better understand its role during brain aging and brain cancer development.

Single-cell sequencing unravels the cellular diversity that shapes neuro- and gliogenesis in the fast aging killifish (N. furzeri) brain

“…We also found other cell types such as newborn neurons (NBN [DCX + , EOMESA + ]), an inhibitory neuron-like mN cluster (Ih-mN6 [GAD1B + , GAD2 + ]) and 5 other mature excitatory neuronal clusters (Ex-mN1/mN2/mN3/mN4/mN5 [SYP + , SLC17A6B + ]) (Figure 5A, 5C, 5D). Interestingly, 4 clusters (Trans-N, NBN, NGP and Inter-NGP) shed more light on neurogenic commitment or a branchpoint with specific expression of MEX3A, a crucial gene that is required for neuroblast proliferation during adult neurogenesis 31,32 . MEX3A was highly expressed in Trans-N/NBN and lower in NGP/Inter-NGP (Figure 5C).…”

The endogenous mex-3 3´UTR is required for germline repression and contributes to optimal fecundity in C. elegans

“…The planarian homologue (mex3-1) maintains the pool of mitotic stem cells in addition to promoting stem cell differentiation [ 35 ]. In Xenopus laevis , mex3A contributes to maintenance of proliferating neuronal stem cells [ 36 ].…”

MEX3A knockdown inhibits the tumorigenesis of colorectal cancer via modulating CDK2 expression

“…Mex-3 RNA binding family member A (MEX3A) was initially identified as a translational regulator in Caenorhabditis elegans, and is typically distributed in early embryos (4). In addition, MEX3A has been characterized as a phosphoprotein that can bind with RNA (5). MEX3A can also regulate target protein ubiquitination via its ring finger domain, which results in the regulation of the target protein subcellular localization and stability (6)(7)(8).…”