Protein kinase CK2 is a ubiquitous protein kinase implicated in proliferation and cell survival. Its regulatory ␤ subunit, CK2␤, which is encoded by a single gene in mammals, has been suspected of regulating other protein kinases. In this work, we show that knockout of the CK2␤ gene in mice leads to postimplantation lethality. Mutant embryos were reduced in size at embryonic day 6.5 (E6.5). They did not exhibit signs of apoptosis but did show reduced cell proliferation. Mutant embryos were resorbed at E7.5. In vitro, CK2␤ ؊/؊ morula development stopped after the blastocyst stage. Attempts to generate homozygous embryonic stem (ES) cells failed. By using a conditional knockout approach, we show that lack of CK2␤ is deleterious for mouse ES cells and primary embryonic fibroblasts. This is in contrast to what occurs with yeast cells, which can survive without functional CK2␤. Thus, our study demonstrates that in mammals, CK2␤ is essential for viability at the cellular level, possibly because it acquired new functions during evolution.Protein kinase CK2 is a pleiotropic and highly conserved protein kinase with more than 300 substrates described to date. It seems to be involved in controlling a large panel of normal cellular functions such as gene expression, protein synthesis, cell cycle, and proliferation, as well as pathological processes such as carcinogenesis and viral tumorigenesis (12, 33). Recently, its function in protecting cells against apoptosis has been reported (1).CK2 is a tetrameric holoenzyme generally composed of two catalytic subunits, ␣ and ␣Ј, and two regulatory ␤ subunits which combine to form an ␣␣Ј␤ 2 , ␣ 2 ␤ 2 , or ␣Ј 2 ␤ 2 heterotetramer. The catalytic CK2 subunits ␣ and ␣Ј belong to the eukaryotic protein kinase superfamily. In contrast, the regulatory ␤ subunit is a unique protein encoded by a single gene in mammals (3) and does not belong to a known protein family.CK2␤ has several functions in the holoenzyme complex. Reconstitution experiments with recombinant purified subunits have demonstrated that CK2␤ modulates the activity of CK2. Depending on the substrate, CK2␤ activates or downregulates the activity of the catalytic subunit (24). CK2␤ also confers stability to the holoenzyme complex (18) and seems to mediate interaction with a number of substrates (19).The crystal structure elucidations of the isolated CK2␤ subunit (5) and of the holoenzyme complex (28) indicate that the ␤ subunit exists as a dimer and is the building block of the CK2 holoenzyme bridging the two catalytic subunits. The crystal structure is also consistent with the suggested flexible role of the ␤ subunit as a docking partner for other protein kinases and other interacting partners in the cell (28).Functional and biochemical studies have indicated that fractions of both the catalytic and regulatory subunits may exist separately. A population of CK2␣ that binds to protein phosphatase 2A is free of CK2␤ (16). Moreover, CK2␤ fractions devoid of the catalytic subunit, but probably involved in complexes with other prote...

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 (CK2␤) in embryonic neural progenitors. Loss of CK2␤ leads to defects in proliferation and differentiation of embryonic NSCs. We establish CK2␤ as a key positive regulator for the development of oligodendrocyte precursor cells (OPCs), both in vivo and in vitro. We show that CK2␤ 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, CK2␤ appears to play an essential and uncompensated role in central nervous system development.Casein kinase 2 (CK2) is a conserved serine/threonine kinase with more than 300 substrates, mostly proteins related to transcription-directed signaling (27). CK2 is a heterotetrameric holoenzyme formed by two catalytic subunits, ␣ and ␣Ј, that associate with a dimeric building block of regulatory ␤ subunits (␣ 2 ␤ 2 ). CK2␤ modulates the substrate specificity of the CK2 enzymatic activity, and its architecture is consistent with its role as a docking partner for other interacting proteins (4). We previously demonstrated that disruption of CK2␤ function in mice results in postimplantation lethality. Moreover, many attempts to generate CK2␤ Ϫ/Ϫ embryonic stem (ES) cells failed, suggesting an essential role of mammalian CK2␤ for ES cell viability (2).The function of CK2␤ for cell cycle progression has been investigated, but its precise role is largely unknown. The cell proliferation function of CK2␤ was first characterized in human fibroblasts, by use of antisense oligodeoxynucleotides and microinjection of specific antibodies (19,26). Recently, a genome-wide survey of protein kinases required for cell progression into cultured Drosophila melanogaster S2 cells by doublestranded RNA demonstrated that CK2␤ is required for centrosomal normality (1). In the same vein, downregulation of CK2␤ by small interfering RNA (siRNA) results in delayed cell cycle progression in cultured mammalian cells (42). Finally, in a genetic screen for mutations affecting the central brain of Drosophila, a hypomorphic allele of D. melanogaster CK2␤ has been isolated, and that study suggested a