CRY2 Is Associated with Depression

Background

Abnormalities in the circadian clockwork often characterize patients with major depressive and bipolar disorders. Circadian clock genes are targets of interest in these patients. CRY2 is a circadian gene that participates in regulation of the evening oscillator. This is of interest in mood disorders where a lack of switch from evening to morning oscillators has been postulated.

Principal Findings

We observed a marked diurnal variation in human CRY2 mRNA levels from peripheral blood mononuclear cells and a significant up-regulation (P = 0.020) following one-night total sleep deprivation, a known antidepressant. In depressed bipolar patients, levels of CRY2 mRNA were decreased (P = 0.029) and a complete lack of increase was observed following sleep deprivation. To investigate a possible genetic contribution, we undertook SNP genotyping of the CRY2 gene in two independent population-based samples from Sweden (118 cases and 1011 controls) and Finland (86 cases and 1096 controls). The CRY2 gene was significantly associated with winter depression in both samples (haplotype analysis in Swedish and Finnish samples: OR = 1.8, P = 0.0059 and OR = 1.8, P = 0.00044, respectively).

Conclusions

We propose that a CRY2 locus is associated with vulnerability for depression, and that mechanisms of action involve dysregulation of CRY2 expression.     

CRY2 Genetic Variants Associate with Dysthymia

People with mood disorders often have disruptions in their circadian rhythms. Recent molecular genetics has linked circadian clock genes to mood disorders. Our objective was to study two core circadian clock genes, CRY1 and CRY2 as well as TTC1 that interacts with CRY2, in relation to depressive and anxiety disorders. Of these three genes, 48 single-nucleotide polymorphisms (SNPs) whose selection was based on the linkage disequilibrium and potential functionality were genotyped in 5910 individuals from a nationwide population-based sample. The diagnoses of major depressive disorder, dysthymia and anxiety disorders were assessed with a structured interview (M-CIDI). In addition, the participants filled in self-report questionnaires on depressive and anxiety symptoms. Logistic and linear regression models were used to analyze the associations of the SNPs with the phenotypes. Four CRY2 genetic variants (rs10838524, rs7121611, rs7945565, rs1401419) associated significantly with dysthymia (false discovery rate q<0.05). This finding together with earlier CRY2 associations with winter depression and with bipolar type 1 disorder supports the view that CRY2 gene has a role in mood disorders.     

CRY2 Is Associated with Rapid Cycling in Bipolar Disorder Patients

Background

Bipolar disorder patients often display abnormalities in circadian rhythm, and they are sensitive to irregular diurnal rhythms. CRY2 participates in the core clock that generates circadian rhythms. CRY2 mRNA expression in blood mononuclear cells was recently shown to display a marked diurnal variation and to respond to total sleep deprivation in healthy human volunteers. It was also shown that bipolar patients in a depressive state had lower CRY2 mRNA levels, nonresponsive to total sleep deprivation, compared to healthy controls, and that CRY2 gene variation was associated with winter depression in both Swedish and Finnish cohorts.

Principal Findings

Four CRY2 SNPs spanning from intron 2 to downstream 3′UTR were analyzed for association to bipolar disorder type 1 (n = 497), bipolar disorder type 2 (n = 60) and bipolar disorder with the feature rapid cycling (n = 155) versus blood donors (n = 1044) in Sweden. Also, the rapid cycling cases were compared with bipolar disorder cases without rapid cycling (n = 422). The haplotype GGAC was underrepresented among rapid cycling cases versus controls and versus bipolar disorder cases without rapid cycling (OR = 0.7, P = 0.006−0.02), whereas overrepresentation among rapid cycling cases was seen for AAAC (OR = 1.3−1.4, P = 0.03−0.04) and AGGA (OR = 1.5, P = 0.05). The risk and protective CRY2 haplotypes and their effect sizes were similar to those recently suggested to be associated with winter depression in Swedes.

Conclusions

We propose that the circadian gene CRY2 is associated with rapid cycling in bipolar disorder. This is the first time a clock gene is implicated in rapid cycling, and one of few findings showing a molecular discrimination between rapid cycling and other forms of bipolar disorder.     

蓝光受体CRY1和CRY2对拟南芥钾吸收影响的研究

以拟南芥野生型Col-4和蓝光受体突变体cry1,cry2和cry1cry2为材料在蓝光下进行缺K+处理,cry1cry2的下胚轴及根的伸长受抑制程度最大.经过对K+充足条件下的Col-4,cry1,cry2和cry1cry2的钾元素含量和持水性检测.以及采用定量PCR对K+转运栽体和离子通道相关基因如AKT1,AtKC1,AKUP1等表达水平的分析,发现cry1cry2的钾元素含量最高、持水性最低,且其K+转运载体和离子通道相关基因的表达量也最高.该结果说明蓝光下CRY1和CRY2的缺失对K+的吸收起促进作用.     

A putative flavin electron transport pathway is differentially utilized in Xenopus CRY1 and CRY2.

Xenopus laevis cryptochromes (xCRYs) can suppress xCLOCK/xBMAL1-mediated activation of a period E box-containing promoter. This suppression is a crucial part of the vertebrate circadian oscillator. Similar to CRYs in other species, as well as to the closely related photolyases, xCRYs have a conserved flavin binding domain. We show here that an intact flavin binding domain is required for normal function. However, it appears that each xCRY may utilize the bound flavin differently. Mutation in any of the three conserved tryptophan residues in the putative electron transport chain inhibits xCRY2b function, while only the mutation in the last of the three tryptophans significantly affects xCRY1 function. Although knockout studies in mice have suggested that CRY1 and CRY2 are not totally redundant, this is the first time that molecular/biochemical differences between CRY1 and CRY2 have been demonstrated. Both CRYs seem to require an intact flavin binding domain, suggesting that electron transport is important in their ability to suppress CLOCK/BMAL1 activation. However, only xCRY2b appears to depend on electron transport through the conserved tryptophan pathway.     

拟南芥中光信号系统中关键基因CRY1、CRY2和COP1启动子的表达模式分析

通过构建表达光信号系统关键基因CRY1、CRY2和COP1启动子与GUS融合基因的拟南芥转基因植株,并对转基因植株进行GUS组织化学染色的结果表明,CRY1、CRY2和COP1的表达模式不受光条件的调控,并且在各器官有广泛的表达。分别分析CRY1基因启动子在cop1突变体以及COP1基因启动子在cry1突变体遗传背景中表达模式的结果表明,CRY1和COP1在转录水平上不存在明显的相互调控关系。     

A putative flavin electron transport pathway is differentially utilized in Xenopus CRY1 and CRY2

Xenopus laevis cryptochromes (xCRYs) can suppress xCLOCK/xBMAL1-mediated activation of a period E box-containing promoter. This suppression is a crucial part of the vertebrate circadian oscillator. Similar to CRYs in other species, as well as to the closely related photolyases, xCRYs have a conserved flavin binding domain. We show here that an intact flavin binding domain is required for normal function. However, it appears that each xCRY may utilize the bound flavin differently. Mutation in any of the three conserved tryptophan residues in the putative electron transport chain inhibits xCRY2b function, while only the mutation in the last of the three tryptophans significantly affects xCRY1 function. Although knockout studies in mice have suggested that CRY1 and CRY2 are not totally redundant [1] and [2], this is the first time that molecular/biochemical differences between CRY1 and CRY2 have been demonstrated. Both CRYs seem to require an intact flavin binding domain, suggesting that electron transport is important in their ability to suppress CLOCK/BMAL1 activation. However, only xCRY2b appears to depend on electron transport through the conserved tryptophan pathway.     

Light-dependent interaction between Drosophila CRY and the clock protein PER mediated by the carboxy terminus of CRY.

BACKGROUND: The biological clock synchronizes the organism with the environment, responding to changes in light and temperature. Drosophila CRYPTOCHROME (CRY), a putative circadian photoreceptor, has previously been reported to interact with the clock protein TIMELESS (TIM) in a light-dependent manner. Although TIM dimerizes with PERIOD (PER), no association between CRY and PER has previously been revealed, and aspects of the light dependence of the TIM/CRY interaction are still unclear. RESULTS: Behavioral analysis of double mutants of per and cry suggested a genetic interaction between the two loci. To investigate whether this was reflected in a physical interaction, we employed a yeast-two-hybrid system that revealed a dimerization between PER and CRY. This was further supported by a coimmunoprecipitation assay in tissue culture cells. We also show that the light-dependent nuclear interactions of PER and TIM with CRY require the C terminus of CRY and may involve a trans-acting repressor. CONCLUSIONS: This study shows that, as in mammals, Drosophila CRY interacts with PER, and, as in plants, the C terminus of CRY is involved in mediating light responses. A model for the light dependence of CRY is discussed.     

Drosophila CRY is a deep brain circadian photoreceptor

cry (cryptochrome) is an important clock gene, and recent data indicate that it encodes a critical circadian photoreceptor in Drosophila. A mutant allele, cry(b), inhibits circadian photoresponses. Restricting CRY expression to specific fly tissues shows that CRY expression is needed in a cell-autonomous fashion for oscillators present in different locations. CRY overexpression in brain pacemaker cells increases behavioral photosensitivity, and this restricted CRY expression also rescues all circadian defects of cry(b) behavior. As wild-type pacemaker neurons express CRY, the results indicate that they make a striking contribution to all aspects of behavioral circadian rhythms and are directly light responsive. These brain neurons therefore contain an identified deep brain photoreceptor, as well as the other circadian elements: a central pace-maker and a behavioral output system.