Casein kinase II

DEVELOPMENTAL BIOLOGY

Embryonic

CkII is present ubiquitously throughout embryogeneis (M. Abu-Shaar and R. S. Mann, personal communication to Jaffe, 1997).

Drosophila CK2 regulates lateral-inhibition during eye and bristle development

Lateral inhibition is critical for cell fate determination and involves the functions of Notch (N) and its effectors, the Enhancer of Split Complex, E(spl)C repressors. Although E(spl) proteins mediate the repressive effects of N in diverse contexts, the role of phosphorylation has been unclear. This study implicates a common role for the highly conserved Ser/Thr protein kinase CK2 during eye and bristle development. Compromising the functions of the catalytic (α) subunit of CK2 elicits a rough eye and defects in the interommatidial bristles (IOBs). These phenotypes are exacerbated by mutations in CK2 and suppressed by an increase in the dosage of this protein kinase. The appearance of the rough eye correlates, in time and space, to the specification and refinement of the ‘founding’ R8 photoreceptor. Consistent with this observation, compromising CK2 elicits supernumerary R8’s at the posterior margin of the morphogenetic furrow (MF), a phenotype characteristic of loss of E(spl)C and impaired lateral inhibition. Compromising CK2 elicits ectopic and split bristles. The former reflects the specification of excess bristle SOPs, while the latter suggests roles during asymmetric divisions that drive morphogenesis of this sensory organ. In addition, these phenotypes are exacerbated by mutations in CK2 or E(spl), indicating genetic interactions between these two loci. Given the centrality of E(spl) to the repressive effects of N, these studies suggest conserved roles for this protein kinase during lateral inhibition. Candidates for this regulation are the E(spl) repressors, the terminal effectors of this pathway (Bose, 2006).

Neurogenesis reflects the outcome of a complex balance between the activities of transcription factors that favor this cell fate (ASC/Ato) and those that oppose it (E(spl)). It is increasingly apparent that formation of the eye and bristle are predicated on a similar mechanistic framework, even though the proneurals that participate in these two developmental programs are distinct. For example, the PNCs in the eye (the R8 cell) require ato, while those in the bristle (macrochaetes and IOBs) require ASC. Nevertheless, one common feature of the resolution of PNCs in the eye and the bristle is the centrality of E(spl)C, since loss of E(spl)C leads to exaggerated neurogenesis in both contexts. In the eye it leads to excess R8’s, rough eyes, and duplicated IOBs, while in the bristles this manifests as ectopic, split and missing bristles. Extensive analyses have identified the genes involved with these developmental programs, the feedback loops that reinforce proneural expression in R8’s/SOPs, and the role of E(spl)C for lateral inhibition. In contrast, it has remained unclear how phosphorylation contributes to the dynamics of this process (Bose, 2006).

It has been thought that transcription of E(spl) is, by itself, necessary and sufficient for lateral inhibition. This model emerged from studies on bristle development, where ectopic E(spl) proteins extinguished the SOPs, whereas loss of E(spl) favored this cell fate. This model needs qualification because similar outcomes have not been recapitulated in the eye. In this context, loss of E(spl) demonstrably compromises lateral inhibition and elicits excess R8’s. However, ectopic expression of E(spl) members does not block the R8 fate, and consequently the eye displays the normal hexagonal packing of the ommatidia; the only defect is loss of the IOBs whose developmental program bears similarities to that of the macrochaetes. In contrast, R8 formation is blocked by the truncated M8* protein encoded by the E(spl)D allele, or by the CK2 phophomimetic variant M8SD. It is important to note that the eye defect of E(spl)D requires N^spl, a recessive allele that attenuates ato, but not E(spl), expression. The inability of M8* to recruit Gro, which compromises repression, thus necessitates a sensitized background, one conferred by N^spl. Accordingly, M8SD (which binds Gro) elicits eye defects independent of N^spl (Karandikar, 2004). Based on the observation that both M8* and M8SD display exacerbated and equivalent interactions with Ato, it was proposed that CK2 phosphorylation switches M8 into an active repressor by uncovering the Orange domain, and it is this regulation that is bypassed by the E(spl)D mutation (Karandikar, 2004). Given that the Orange domain mediates binding to other proneurals as well, this regulation by CK2 should have been more general to lateral inhibition. These studies suggest just such a role in the eye and the bristle (Bose, 2006).

This work supports the notion that CK2 is a participant in lateral inhibition. Compromising CK2 by a number of independent routes, i.e., in wild type and backgrounds mutant for CK2 and E(spl), elicits neural defects in the eye and bristle. These include rough eyes due to the specification of excess 'founding' R8 cells, and ectopic bristles (macrochaetes and IOBs) due to the specification of excess SOP’s. These phenotypes are hallmarks of impaired lateral inhibition, and have been previously described for loss of function of the E(spl)C. Evidence is provided for genetic interactions between CK2 and E(spl). While these studies provide multiple lines of evidence, the absence of suitable antibodies have precluded a formal demonstration that E(spl) repressors are, in fact, phosphorylated in cells undergoing lateral inhibition. Nevertheless, the congruence of the results utilizing CK2-RNAi or CK2-DN in conjunction with extant mutants and cell fate in imaginal discs, together, constitute a plausible argument supporting a role for this protein kinase (Bose, 2006).

These studies also suggest secondary roles for CK2 in the bristle lineage. In contrast to R8 patterning, the roles of N and E(spl) are different during bristle morphogenesis. In the case of the macrochaete or the IOB, N and E(spl) are re-deployed following SOP selection. Specifically, the SOP gives rise to the pI neuroblast that undergoes two asymmetric divisions to generate four cell types characteristic of the sensillum; socket, shaft, sheath and neuron, and these divisions are dependent on N- and E(spl)-inhibitory signaling. Thus loss of E(spl) following SOP selection manifests as split bristles (aberrant division of the pIIa cell) or missing bristles (aberrant division of the pI cell). The split bristles described thus suggest a role for CK2 during the socket-to-shaft sister cell fate. In contrast, while the missing bristles suggest a role for CK2 during the pIIa-vs-pIIb fates, this phenotype could result from loss of the SOP itself, a possibility if CK2 levels become rate limiting for cell division. Despite the fact that the timing of the asymmetric divisions of pI, pIIa and pIIb are well known, CK2-RNAi or CK2-DN are not suitable for dissecting the roles of CK2 at these later steps of bristle development. Conditional alleles of CK2, e.g., temperature-sensitives, will be necessary to better define its roles during specification of these sister-cell fates. One major question that emerges from these studies is why is phosphorylation necessary, given that not all members of the E(spl)C are targets of CK2. It is thought that evolutionary principles, the diversities and/or affinities of interactions between E(spl)C and ASC/ato, and their spatial expression patterns, perhaps, offer insights (Bose, 2006).

Of the seven E(spl) proteins, three (M8, M5, and M7) are targeted by CK2, and these are also the most closely related. Among all E(spl) members, two regions largely account for length heterogeneity and divergence. These are sequences between HLH and Orange and those between Orange and WRPW, the CtD. However, within the CtD of M8 (and M5 and M7 as well) is a highly invariant sequence, the phosphorylation domain (P-domain) that harbors the CK2 site. Given the phylogenetic relationships of these species, it is noteworthy that over a period of ~50 million years the P-domain and the CK2 site have been remarkably conserved. For example, of all M8 homologs, only D. pseudoobscura, D. grimshawii and D. hydei harbor a Glu residue, in place of Asp, at the n + 3 position of the CK2 phosphoacceptor. While it has not been experimentally confirmed that these homologs are phosphorylated, the possibility is high because this change still conforms to the consensus (S/T-D/E-x-D/E) for recognition by CK2. The virtually identical consensus site that is present in mammalian Hes6 is targeted by CK2 (Gratton, 2003) in vivo (Bose, 2006).

The mechanisms by which E(spl) proteins mediate repression have been intensely studied. In essence, E(spl) proteins repress ASC/Ato. Repression was initially thought to involve binding to a DNA sequence, the N-box. This, however, is not the case, because E(spl) proteins neutralized for DNA-binding still function as potent repressors. Furthermore, no N-box has been found in the regulatory region of ato, while that in sc is dispensable for repression in non-SOPs. It is now thought that direct (protein–protein) interactions between E(spl) and proneurals are more critical for repression, the protein–tether model (Giagtzoglou, 2003). In this model, repression by E(spl) occurs via direct interactions with enhancer bound proneurals, rather than by activator sequestration. This model is consistent with direct interactions between E(spl) and ASC/Ato proteins. It was, in fact, the analyses of various binary combinations that were the first to suggest that these interactions are regulated and non-redundant, two aspects that appear relevant to the current findings (Bose, 2006).

Analysis of M8 and its E(spl)D encoded variant, M8* provided the first hint that these antagonistic interactions are regulated. For example, it has been reported that, in addition to Ato, M8* interacts with a much higher affinity with Ac, Sc, and Ase. A similar case is described for M8SD, which interacts with Ato or L’sc with affinities significantly higher than M8 or its non-phosphorylatable variant M8SA (Karandikar, 2004). It is noteworthy that phosphorylation of mammalian Hes6 by CK2 is also a pre-requisite for its interactions with Hes1 (Gratton, 2003). Thus CK2 phosphorylation influences antagonistic interactions between the E(spl) and the ASC/Ato. Because these studies have employed two hybrid, instead of direct protein, approaches the possibility that these are kinetic effects remains open. This interpretation is consistent with the observations that a 2× dosage of a UAS-mδ construct interferes with Ato and blocks eye development in the wild type, whereas that of m7, m5 or m8 requires N^spl. Together, these findings argue that E(spl)-ASC interactions are of variable strengths and are isoform-specific. Given that only a subset of E(spl) and ASC members are expressed in the eye and wing disc, the possibility thus arises that distinct domains of ASC define sub-regions of the proneural field. In this context, E(spl) members might have been selected based on their affinities and/or specificities for these proneural factors. Thus the type of E(spl) repressors that are deployed might reflect the combinations and levels of proneurals, with CK2 playing an integrative role. The currently available techniques preclude a distinction between these possibilities (Bose, 2006).

It is presently unclear if/how CK2 activity is modulated during neurogenesis. Expression of this enzyme appears to be constitutive in the eye and wing disc (Karandikar, 2004). Holoenzyme formation, proposed to be a dynamic process in vivo, represents an attractive regulatory mechanism, given that CK2β modulates substrate recognition and that the fly CK2β gene encodes for non-redundant isoforms of this regulatory subunit. Alternatively, CK2 might be regulated by assembly into multiprotein complexes and/or via interactions with protein phosphatases. Such a coordinated function has been described for regulation of Period, the central component of the circadian clock, by CK2 and the phosphatase PP2A. Future studies aimed at the identification of protein phosphatase(s) that counteract the phosphorylation of E(spl)m8/5/7 by CK2, or multiprotein complexes containing E(spl) and/or CK2 will be required to better define the regulatory dynamics of this process during eye and bristle development (Bose, 2006).

Effects of Mutation

The posttranslational modification of clock proteins is critical for the function of circadian oscillators. By genetic analysis of a Drosophila melanogaster circadian clock mutant known as Andante, which has abnormally long circadian periods, it has been shown that Casein kinase 2 (CK2) has a role in determining period length. Andante is a mutation of the gene encoding the ß subunit of CK2 and is predicted to perturb CK2ß subunit dimerization. It is associated with reduced ß subunit levels, indicative of a defect in alpha:ß association and production of the tetrameric alpha2:ß2 holoenzyme. Consistent with a direct action on the clock mechanism, it has been shown that CK2ß is localized within clock neurons and that the clock proteins Period (Per) and Timeless (Tim) accumulate to abnormally high levels in the Andante mutant. Furthermore, the nuclear translocation of Per and Tim is delayed in Andante, and this defect accounts for the long-period phenotype of the mutant. These results suggest a function for CK2-dependent phosphorylation in the molecular oscillator (Akten, 2003).

It is of interest that the Andante mutation affects the nuclear entry of clock proteins in the small LN_v population, but seems to have no effect on the large LN_v neurons. Such a differential effect suggests that CK2 is important for oscillator function in one population but not the other. Indeed, the small LN_v cells have been shown to be critical for the clock regulation of activity rhythms; the small cells send projections to a region of the dorsal brain implicated in clock output, and there is a circadian rhythm in the release of the clock output factor pigment dispersing factor (PDF) in these dorsal projections. Furthermore, it has been reported that the small but not the large LN_v cells show Tim rhythmicity in constant darkness (DD). Finally, there are differences between the large and small LN_v cells, with regard to the timing of Per and Tim nuclear entry. As CK2 deficits seem only to affect nuclear entry in the small LN_v neurons, it is possible that this kinase regulates differences between the two neuronal populations (Akten, 2003).

Although it is likely that CK2 acts within clock cells to help specify period length, these studies indicate neither the cellular compartment in which the kinase acts nor the molecular substrates of the enzyme that are relevant for clock function. A delay in the nuclear accumulation of clock proteins, as seen in Andante, suggests that the kinase functions in the cytoplasm to promote nuclear entry. This function might be mediated by direct phosphorylation of a clock protein (such as Per or Tim) or by activation of a second kinase such as GSK-3/Shaggy, which has been implicated in promoting the nuclear entry of Tim. The elevated levels of Per and Tim observed in Andante suggest a decreased turnover of the clock proteins, and this might arise because of a defect in the targeted degradation of one or both proteins within the nucleus. Similar to the Doubletime kinase, CK2 might act both in the cytoplasm and nucleus of clock cells to determine the timing of nuclear entry and/or stability of clock proteins (Akten, 2003).

These studies of CK2 in Drosophila suggest that this kinase might have an important role in the regulation of circadian period in other animal species. Previous studies in the plant Arabidopsis and the fungus Neurospora have also implicated CK2 activity in circadian oscillator function. The Arabidopsis study showed that overexpression of the CK2ß3 subunit is associated with a shortening of circadian period, a result similar to that obtained in this study of Drosophila CK2ß. The Neurospora study showed abnormal phosphorylation of the Frequency (Frq) protein in a Neurospora CK2alpha mutant, but circadian behavior (such as conidiation rhythms) could not be examined in that study because of reduced viability. Although neither of these previous reports characterize a mutant with decreased CK2 activity, the results are consistent with studies of Andante and indicate an evolutionarily conserved role for CK2 in circadian oscillator function (Akten, 2003).

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date revised: 25 November 2012

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