ABSTRACT
Programs that govern stem cell maintenance and pluripotency are dependent on extracellular factors and of intrinsic cell modulators. Embryonic stem (ES) cells with a specific depletion of the gene encoding the regulatory subunit of protein kinase CK2 (CK2ß) revealed a viability defect. However, analysis of CK2ß functions along the neural lineage established CK2ß as a positive regulator for neural stem/progenitor cell (NSC) proliferation and multipotency. By using an in vitro genetic conditional approach, we demonstrate in this work that specific domains of CK2ß involved in the regulatory function towards CK2 catalytic subunits are crucial structural determinants for ES cell homeostasis.
Subject(s)
Casein Kinase II/chemistry , Casein Kinase II/metabolism , Embryonic Stem Cells/enzymology , Animals , Catalytic Domain , Cell Differentiation , Cell Lineage , Cell Proliferation , Cell Survival , Embryonic Stem Cells/cytology , Mice , Mutant Proteins/chemistry , Mutant Proteins/metabolism , Mutation/genetics , Neural Stem Cells/cytology , Neural Stem Cells/enzymology , Oligodendroglia/cytology , Oligodendroglia/metabolism , Structure-Activity Relationship , Teratoma/pathologyABSTRACT
Genetic programs that govern neural stem/progenitor cell (NSC) proliferation and differentiation are dependent on extracellular cues and a network of transcription factors, which can be regulated posttranslationally by phosphorylation. However, little is known about the kinase-dependent pathways regulating NSC maintenance and oligodendrocyte development. We used a conditional knockout approach to target the murine regulatory subunit (beta) of protein kinase casein kinase 2 (CK2beta) in embryonic neural progenitors. Loss of CK2beta leads to defects in proliferation and differentiation of embryonic NSCs. We establish CK2beta as a key positive regulator for the development of oligodendrocyte precursor cells (OPCs), both in vivo and in vitro. We show that CK2beta directly interacts with the basic helix-loop-helix (bHLH) transcription factor Olig2, a critical modulator of OPC development, and activates the CK2-dependent phosphorylation of its serine-threonine-rich (STR) domain. Finally, we reveal that the CK2-targeted STR domain is required for the oligodendroglial function of Olig2. These findings suggest that CK2 may control oligodendrogenesis, in part, by regulating the activity of the lineage-specific transcription factor Olig2. Thus, CK2beta appears to play an essential and uncompensated role in central nervous system development.
