Psychiatry related information on dco

• We have isolated a new dbt allele, dbt(ar), which causes arrhythmic locomotor activity in homozygous viable adults, as well as molecular arrhythmicity, with constitutively high levels of PER proteins, and low levels of TIMELESS (TIM) proteins [1].

High impact information on dco

• Molecular and genetic characterizations of circadian rhythms in Drosophila indicate that function of an intracellular pacemaker requires the activities of proteins encoded by three genes: period (per), timeless (tim), and doubletime (dbt) [2].
• A third allele, dbtP, causes pupal lethality and eliminates circadian cycling of per and tim gene products in larvae [3].
• DBT is capable of binding to PER in vitro and in Drosophila cells, suggesting that a physical association of PER and DBT regulates PER phosphorylation and accumulation in vivo [4].
• This was first shown in Drosophila with the characterization of Doubletime (Dbt), a homologue of vertebrate casein kinase Iepsilon [5].
• Per and Tim undergo rhythmic changes in phosphorylation, and evidence supports roles for two kinases in this process: Doubletime (Dbt) phosphorylates Per, whereas Shaggy (Sgg) phosphorylates Tim [6].

Biological context of dco

• Drosophila doubletime mutations which either shorten or lengthen the period of circadian rhythms decrease the protein kinase activity of casein kinase I [7].
• Analysis of their phenotypes and molecular lesions suggests that the Discs overgrown protein is a crucial component in the mechanism that links cell survival during proliferation to growth arrest in imaginal discs [8].
• double-time is identical to discs overgrown, which is required for cell survival, proliferation and growth arrest in Drosophila imaginal discs [8].
• By examining hypomorphic mutations of the Drosophila CKIepsilon homolog discs overgrown (dco)/double-time, we now show that it is an essential component of the noncanonical/planar cell polarity pathway [9].
• Identification of a missense mutation in CKIepsilon as the tau mutation in the Syrian hamster places CKIepsilon within the core clock machinery in mammals [10].

Anatomical context of dco

• In the present study, the expression profiles of CKIepsilon and CKIdelta mRNAs were examined in the mice clock center, suprachiasmatic nucleus (SCN) [11].
• In situ hybridization showed presumably identical distribution of dbt, CKI[.alpha], and per transcripts in the putative clock neurons of the head ganglia, as well as in the retina, where CKI-and PER-like immunoreactivities were colocalized, suggesting a possible involvement of both CKIs in the B. mori circadian system [12].
• One allele of dco (dcole88) prevents egg development when homozygous in the germ line, whereas the dco18 allele has no effect on germ-line development [13].
• Chimeras and mosaics were produced in which developing oocytes and nurse cells were mutant at one of five imaginal disc overgrowth loci (fat, lgd, lgl, c43 and dco) while the enveloping follicle cells were normal [13].

Associations of dco with chemical compounds

• Yet Sgg and Dbt often require a phosphoserine in their target site, and analysis of Per phosphorylation in dbt mutants suggests a role for other kinases [6].
• Genetic studies in Drosophila have identified double-time (dbt), a serine/threonine protein kinase that is highly homologous to human casein kinase I epsilon (CKIepsilon), as the first kinase linked to behavioral rhythms [10].
• Based on staining with PY and DIg antibodies, the apico-lateral junctional complexes appeared normal in tissue from the hyperplastic overgrowth mutants fat, dco, gd and wts [14].
• Sensitization to repeated cocaine exposures, a phenomenon also seen in humans and animal models and associated with enhanced drug craving, is eliminated in flies mutant for period, clock, cycle, and doubletime, but not in flies lacking the gene timeless [15].
• Moreover, lithium also lengthens the period in GSK-3beta heterozygous mutants and doubletime long mutants [16].

Regulatory relationships of dco

• We find that increased CKIepsilon stimulates whereas dominant-negative or a null CKIepsilon mutation inhibits Wg signaling [17].

Other interactions of dco

• The Drosophila PERIOD (dPER) protein is phosphorylated by the serine?threonine protein kinase, DOUBLETIME (DBT) [18].
• Mutations in dco result in a reduced level of Dishevelled phosphorylation in vivo [9].
• The predicted amino acid sequence shares 70% identity with the catalytic domain of the mammalian delta and epsilon isoforms, Drosophila CKIepsilon and Schizosaccharomyces pombe Hhp1, and 63% identity with Hrr25, a 57-kDa form of yeast CK involved in DNA repair [19].
• Two of these mutants, dlg and dco, show abnormally strong immunoreactivity for allatotropin during the extended larval period and the former also show increased staining with the PTTH antibody [20].

Analytical, diagnostic and therapeutic context of dco

• Here we show, using a cell culture system, that Dbt promotes the progressive phosphorylation of Per, leading to the rapid degradation of hyperphosphorylated isoforms by the ubiquitin-proteasome pathway [5].

References