microRNA regulation of adult neural stem cells

One constant theme of these GEITP pages is the contribution — of genetics, epigenetic factors, environmental effects, endogenous influences, and the microbiome — to any multifactorial trait (phenotype). Multifactorial traits include complex diseases (e.g. schizophrenia, obesity), quantitative traits (e.g. height, body mass index), and responses to drugs as well as to various environmental toxicants. Epigenetic factors include DNA methylation, RNA interference (microRNA regulation), histone modifications, and chromatin remodeling. The former two categories are quite well understood and assays are available, whereas the latter two currently remain poorly understood and are under intensive study.

Adult neural stem cells (NSCs) are located in few specific and restricted niches of the mammalian brain, and they generate neurons throughout the life of the animal. Lifelong neurogenesis (ability to generate new nerve cells) in the adult brain relies on a population of quiescent NSCs (qNSCs), set apart during development. Upon “activation” within the adult brain, the vast majority of these once quiescent cells will produce only a few cohorts of neurons before being depleted, or returning to quiescence. Therefore, an important cornerstone in understanding the regulation of neurogenesis within the adult brain — including its age-related decline — is to decipher mechanisms controlling the balance between qNSC maintenance and activation.

Authors [see attached article] identified a post-transcriptional control mechanism (recall that DNA is transcribed into RNA; RNA is then translated into protein), centered around microRNA 204 (miR-204). As one category of epigenetic factors, microRNAs represent a form of RNA-interference (RNAi) that ties up messenger RNAs (mRNAs) from specific sets of genes, thereby controlling gene expression post-transcriptionally. miR-204 is known to regulate a spectrum of transcripts involved in cell-cycle regulation, nerve-cell migration, and differentiation in qNSCs; miR-204 was found specifically to govern, or maintain, levels of qNSCs. When miR-204 was inhibited, the number of qNSCs in a particular region of the brain [the subependymal zone (SEZ)] was decreased — by inducing premature activation and differentiation of NSCs.

Authors identified the choroid plexus of the mouse lateral ventricle as the major source of miR-204 — which is then released into the cerebrospinal fluid to control the number of NSCs within the SEZ. Thus, these data describe a novel mechanism for maintaining adult somatic stem cells — by a “niche-specific” miRNA that is involved in repressing activation and differentiation of stem cells. 😊



· The EMBO J 2019; 38: e100481

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