Phosphorylation Regulates OLIG2 Cofactor Choice and the Motor Neuron-Oligodendrocyte Fate Switch

Abstract

SummaryA fundamental feature of central nervous system development is that neurons are generated before glia. In the embryonic spinal cord, for example, a group of neuroepithelial stem cells (NSCs) generates motor neurons (MNs), before switching abruptly to oligodendrocyte precursors (OLPs). We asked how transcription factor OLIG2 participates in this MN-OLP fate switch. We found that Serine 147 in the helix-loop-helix domain of OLIG2 was phosphorylated during MN production and dephosphorylated at the onset of OLP genesis. Mutating Serine 147 to Alanine (S147A) abolished MN production without preventing OLP production in transgenic mice, chicks, or cultured P19 cells. We conclude that S147 phosphorylation, possibly by protein kinase A, is required for MN but not OLP genesis and propose that dephosphorylation triggers the MN-OLP switch. Wild-type OLIG2 forms stable homodimers, whereas mutant (unphosphorylated) OLIG2S147A prefers to form heterodimers with Neurogenin 2 or other bHLH partners, suggesting a molecular basis for the switch.

Transcription factor Olig2 defines subpopulations of retinal progenitor cells biased toward specific cell fates

“…5) provides a possible explanation, because these genes might have redundant roles with Olig2. The presence of the bHLH gene, Ngn2, in some Olig2-expressing cells is also of interest because it can partner with Olig2 elsewhere in the CNS (49). A role for Olig2 in cell-fate decisions will require more precise analyses of gain-and loss-of-function experiments, likely in conjuction with manipulations of other bHLH genes.…”

Transcription factor induction of human oligodendrocyte progenitor fate and differentiation

“…Interestingly, coinfection with SOX10 and OLIG2 viruses did not result in a significant increase in O4 + oligodendrocyte differentiation, suggesting that OLIG2 is not the sole limiting factor for OPC fate induction by SOX10. Indeed, because both binding partners (37) and phosphorylation state (38) can regulate the function of OLIG2, overexpression of OLIG2 alone might not provide the correct cellular context for induction of OPC fate.…”

An Amino Terminal Phosphorylation Motif Regulates Intranuclear Compartmentalization of Olig2 in Neural Progenitor Cells

“…To date, there has been no evidence that the anti-p53 activity of phosphorylated Olig2 is actually linked to its function as an E-box binding transcription factor. For example, key genetic functions of the p53 protein are regulated by acetylation (Barlev et al, 2001;Li et al, 2002), and a differential acetylation state of p53 was noted in wild-type relative to Olig2-null neural progenitors. This differential acetylation state would be consistent with a model wherein Olig2 simply competes with p53 for an important coregulator protein that facilitates acetylation .…”

“…Transcription factors within the bHLH family typically function as homodimers or heterodimers to bind canonical E-box promoter elements at target loci. Olig2 and also other bHLH factors (e.g., Neurogenin and Twist) have phosphorylation sites within the bHLH domain that regulate dimerization and interactions with key coregulator proteins (Firulli et al, 2007;Ma et al, 2008;Li et al, 2011). However, it is not self-evident how the phosphorylation state of the Olig2 triple serine motif, located Ͼ100 amino acids proximal to the DNAtargeting bHLH domain, might regulate these functions.…”