The Basic Helix-Loop-Helix Transcription Factors in Neural Differentiation

Abstract

During the development of the central nervous system, neural stem cells initially expand their own population by symmetric cell divisions, in which both progeny re-enter the cell cycle. By mid-gestation, the cells initiate neurogenesis by adopting a mode of asymmetric cell division, in which one daughter cell differentiates into a neuron while the other continues to cycle in the ventricular zone. Neural stem cells gradually alter their characteristics during development and thus give rise to different types of neurons over time, and finally switch to gliogenesis. The basic helix-loop-helix (bHLH) genes coordinately govern these processes and play a key role in the fate choice and the cell diversity. The repressor-type bHLH gene Hes is essential for maintenance of neural stem cells. Hes genes antagonize the activator-type bHLH genes such as Mash1, Math, and Neurogenin (Ngn), which induce neuronal differentiation by activating the neuronal-specific genes. The activator-type bHLH genes not only promote the neuronal fate determination but also regulate the neuronal subtype specification. They also induce expression of Notch ligands such as Delta, which activate Notch signaling and upregulate Hes1 and Hes5 expression in neighboring cells, thereby maintaining these cells undifferentiated. Thus, the activator-type and repressor-type bHLH genes regulate each other, allowing only subsets of cells to undergo differentiation while keeping others to stay neural stem cells. This regulation is essential for generation of complex brain structures of appropriate size, shape, and cell arrangement.