Transcription factors and neural stem cell self-renewal, growth and differentiation

Abstract

The central nervous system (CNS) is a large network of interconnecting and intercommunicating cells that form functional circuits. Disease and injury of the CNS are prominent features of the healthcare landscape. There is an urgent unmet need to generate therapeutic solutions for CNS disease/injury. To increase our understanding of the CNS we need to generate cellular models that are experimentally tractable. Neural stem cells (NSCs), cells that generate the CNS during embryonic development, have been identified and propagated in vitro. To develop NSCs as a cellular model for the CNS we need to understand more about their genetics and cell biology. In particular, we need to define the mechanisms of self-renewal, proliferation and differentiation--i.e. NSC behavior. The analysis of pluripotency of embryonic stem cells through mapping regulatory networks of transcription factors has proven to be a powerful approach to understanding embryonic development. Here, we discuss the role of transcription factors in NSC behavior.

Figure 1

(A) TFs and NSC behavior. The figure outlines NSC behavior and the TFs involved in each step. The starting cell (yellow) that gives rise to neurospheres is likely to be a NSC. What defines ‘stemness’ in the context of the NSC is currently unknown. The NSC undergoing ‘self-renewal’ generates a copy of itself. The next phase is proliferation where NSCs generate NPs (blue) and a neurosphere forms. A number of TFs are implicated in repression of differentiation of these NPs keeping the neurosphere growing. If differentiation signals are imposed the NSCs/NPs leave the cell cycle and form committed progenitors (light brown, green and blue) which then go on to form terminally differentiated cells; neurons, astrocytes and oligodendendrocytes (dark brown, green and blue). The TFs implicated in each of the steps are placed in brackets. For further information on TFs see Tables 1–4 and text. (B) Overlapping functions of TFs. The three processes that are involved in neurosphere formation are presented as circles in a Venn diagram. Self-renewal—blue, proliferation—green and repression of differentiation—red. Overlap in circles shows TFs that have more than one function.