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Abstract
Historically, the mammalian brain was thought to lack stem cells as no new neurons were found to be made in adulthood. That dogma changed ∼25 years ago with the identification of neural stem cells (NSCs) in the adult rodent forebrain. However, unlike rapidly self-renewing mature tissues (e.g., blood, intestinal crypts, skin), the majority of adult NSCs are quiescent, and those that become ‘activated’ are restricted to a few neurogenic zones that repopulate specific brain regions. Conversely, embryonic NSCs are actively proliferating and neurogenic. Investigations into the molecular control of the quiescence-to-proliferation-to-differentiation continuum in the embryonic and adult brain have identified proneural genes encoding basic-helix-loop-helix (bHLH) transcription factors (TFs) as critical regulators. These bHLH TFs initiate genetic programs that remove NSCs from quiescence and drive daughter neural progenitor cells (NPCs) to differentiate into specific neural cell subtypes, thereby contributing to the enormous cellular diversity of the adult brain. However, new insights have revealed that proneural gene activities are context-dependent and tightly regulated. Here we review how proneural bHLH TFs are regulated, with a focus on the murine cerebral cortex, drawing parallels where appropriate to other organisms and neural tissues. We discuss upstream regulatory events, post-translational modifications (phosphorylation, ubiquitinylation), protein–protein interactions, epigenetic and metabolic mechanisms that govern bHLH TF expression, stability, localization, and consequent transactivation of downstream target genes. These tight regulatory controls help to explain paradoxical findings of changes to bHLH activity in different cellular contexts.
Highlights
One-hundred years ago, Santiago Ramon y Cajal likened the pyramidal cells of the cerebral cortex to “a garden filled with innumerable trees. . .which can multiply their branches thanks to intelligent cultivation, send their roots deeper, and produce more exquisite flowers and fruits every day” (Jones, 1994)
Proneural transcription factors (TFs) are critical regulators of neural cell differentiation and subtype specification, contributing to the enormous cellular diversity observed in the cortex
It holds that proneural TFs are themselves tightly regulated, and these interplaying mechanisms of regulation are being elucidated by the scientific community
Summary
One-hundred years ago, Santiago Ramon y Cajal likened the pyramidal cells of the cerebral cortex to “a garden filled with innumerable trees. . .which can multiply their branches thanks to intelligent cultivation, send their roots deeper, and produce more exquisite flowers and fruits every day” (Jones, 1994). Cortical Proneural Gene Regulation architecture and cellular diversity of the cerebral cortex It follows, that one of the most dominant inquiries in developmental neuroscience has been how this enormous cellular diversity is established and choreographed during brain development. Cortical territories are found in all mammals, but display enormous structural diversity across species, transitioning during evolution between smooth (lissencephalic) structures in smaller mammals such as rodents, to highly folded (gyrencephalic) structures in most extant primates and larger mammals (Lewitus et al, 2014) These gross structural differences arise due to species-specific differences in the regulatory events that control self-renewal, proliferation, mode of division (symmetric, asymmetric) and differentiation properties of neural stem cells (NSCs) and their daughter neural progenitor cells (NPCs). Unless otherwise specified, the animal work cited was conducted using murine transgenic models, tissues or cells
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