Abstract
The differentiation of stem cells into the more than 100 billion neurons that compose the central nervous system (CNS) is one of the most remarkable transformations during vertebrate development. A central problem of this process is how neural lineage selection initially is specified in pluripotent stem cells and maintained during the course of neurogenesis. This thesis focuses on how different Sox transcription factors of the HMG-box family control neural cell-type restricted gene expression from the early lineage specification stages to later stages of neuronal maturation.
In the two papers on which this thesis is based, we present a molecular pathway where diverse Sox proteins can act to coordinate neural gene expression as development proceeds, from the early neural lineage specification in pluripotent stem cells to the gene regulatory control operating in maturing postmitotic neurons. We show that, already in pluripotent stem cells, Sox2 binds to inactive neural genes and that, in neural progenitors, Sox3 "takes over" and binds to activated neural genes, but also to silent genes destined to become active in maturing postmitotic neurons. Finally, in postmitotic neurons these genes are bound by Sox11. The binding of Sox3 to silent genes is associated with bivalently marked chromatin domains, containing both trimethylated H3K4 and H3K27, which is resolved to an active state upon Sox11 binding.
Proneural basic helix-loop-helix (bHLH) transcription factors have key roles in promoting NPCs to commit to a differentiation program leading to the generation of post-mitotic neurons. It is shown that Sox4 and Sox11 act downstream of proneural bHLH proteins and are of critical importance for the activation of neuronal protein expression but not for cell cycle withdrawal.
Together these data reveal a regulatory logic whereby sequentially acting Sox transcription factors preselect transcriptional programs that are destined to be activated at later stages of neural differentiation. Thus, a single family of transcription factors acts to coordinate neural gene expression from the early lineage specification to later stages of neural development.
