Neural transcription factors: from embryos to neural stem cells

Abstract

The early steps of neural development in the vertebrate embryo are regulated by sets of transcription factors that control the induction of proliferative, pluripotent neural precursors, the expansion of neural plate stem cells, and their transition to differentiating neural progenitors. These early events are critical for producing a pool of multipotent cells capable of giving rise to the multitude of neurons and glia that form the central nervous system. In this review we summarize findings from gain- and loss-of-function studies in embryos that detail the gene regulatory network responsible for these early events. We discuss whether this information is likely to be similar in mammalian embryonic and induced pluripotent stem cells that are cultured according to protocols designed to produce neurons. The similarities and differences between the embryo and stem cells may provide important guidance to stem cell protocols designed to create immature neural cells for therapeutic uses.

Keywords: Foxd4; neural cell fate; neural induction; neural plate stem cells; neural progenitor cells.

Fig. 1.

A schematic representation of main signaling pathways involved in NTFs development during embryogenesis. Five major signaling pathways including SHH, BMP, WNT, Notch ligands and FGF2, together crosstalk is represented. SHH ligand relieves the constitutive repression of the seven-pass receptor smoothened (SMO) by the modulation of the GLI transcriptional activators Gli1/2. Extracellular regulation of BMP signaling BMP induces the dimerization and then tetramerization of BMP receptors, leading to phosphorylation of the cytoplasmic signal transducer SMAD. WNT signaling activates β-catenin by modulating Frizzed and Dsh. Transcription factor LEF is required for enhancing of E2F1, consequently block Bmi1. The Notch and FGF2 signaling pathways have been implicated in regulating the neural differentiation and development. Notch interacts with NICD and mediates the effect of Hes1 and Gli/12. FGF2 activates JNK through binding with FGFR receptors, thus activating ATF2 regulatory mechanisms in neural development.

Fig. 2.

A gene regulatory network of neural transcription factors that regulate the earliest steps in vertebrate neural development. Foxd4 is required for the expression of the remaining genes, and it directly activates Geminin, Zic2 and Sox11 (blue arrows). Together, these three genes mediate the downstream effects of Foxd4, which is to delay the expression of neural plate stem cell genes (Sox) and repress the expression of neural progenitor genes (Irx, Zic, bHLH).