Specifying Neuronal Cell Identities in the Central Nervous System: A Complex Tale of Proneural Gene Regulation

Abstract

The brain is characterized by an astounding diversity of neuronal phenotypes. In the last few decades, great strides have been made toward understanding how neurons acquire their specific identities during development, revealing a central role for intrinsic and extrinsic factors. Among the most important intrinsic determinants of neural cell fates are the proneural basic-helix-loop-helix (bHLH) transcription factors (TFs). Proneural TFs have been conserved from fly to man and are essential determinants of neural cell fate choice throughout the developing peripheral (PNS) and central (CNS) nervous systems. However, an oft ignored feature of proneural TFs is the tight regulatory controls that limit their activities to precise developmental time points and brain regions and can even change their functions over time. Understanding proneural gene function has required a comprehensive investigation of the intrinsic status of the neural progenitor cells (NPCs) in which they are expressed, including transcriptomic, epigenomic, and metabolic features, but also of the environment to which they are exposed. Here we provide an overview of how proneural genes guide cell fate decisions during nervous system development, highlighting the regulatory controls that control and alter their activities over time. Our main focus is on the developing murine neocortex, with contrasting or confirmatory points raised in other tissues or species when informative. Finally, we end with a forward-looking perspective of how our foundational knowledge of bHLH gene function has allowed for these TFs to be exploited for brain repair via direct neuronal reprogramming, highlighting the importance of understanding their regulatory features.