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Circadian Clock Dysfunction and Psychiatric Disease: Could Fruit Flies have a Say?

Zordan MA, Sandrelli F - Front Neurol (2015)

Bottom Line: Disruption of clock genes and/or the clock network might be related to the etiology of these pathologies; also, some genes, known for their circadian clock functions, might be associated to mental illnesses through clock-independent pleiotropy.There is evidence that the Drosophila brain shares some homologies with the vertebrate cerebellum, basal ganglia, and hypothalamus-pituitary-adrenal axis, the dysfunctions of which have been tied to mental illness.We sum up current knowledge on behavioral endophenotypes, which are amenable to modeling in flies, such as defects involving sleep, cognition, or social interactions, and discuss the relationship of the circadian system to these traits.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of Padova , Padova , Italy ; Cognitive Neuroscience Center, University of Padova , Padova , Italy.

ABSTRACT
There is evidence of a link between the circadian system and psychiatric diseases. Studies in humans and mammals suggest that environmental and/or genetic disruption of the circadian system leads to an increased liability to psychiatric disease. Disruption of clock genes and/or the clock network might be related to the etiology of these pathologies; also, some genes, known for their circadian clock functions, might be associated to mental illnesses through clock-independent pleiotropy. Here, we examine the features which we believe make Drosophila melanogaster a model apt to study the role of the circadian clock in psychiatric disease. Despite differences in the organization of the clock system, the molecular architecture of the Drosophila and mammalian circadian oscillators are comparable and many components are evolutionarily related. In addition, Drosophila has a rather complex nervous system, which shares much at the cell and neurobiological level with humans, i.e., a tripartite brain, the main neurotransmitter systems, and behavioral traits: circadian behavior, learning and memory, motivation, addiction, social behavior. There is evidence that the Drosophila brain shares some homologies with the vertebrate cerebellum, basal ganglia, and hypothalamus-pituitary-adrenal axis, the dysfunctions of which have been tied to mental illness. We discuss Drosophila in comparison to mammals with reference to the: organization of the brain and neurotransmitter systems; architecture of the circadian clock; clock-controlled behaviors. We sum up current knowledge on behavioral endophenotypes, which are amenable to modeling in flies, such as defects involving sleep, cognition, or social interactions, and discuss the relationship of the circadian system to these traits. Finally, we consider if Drosophila could be a valuable asset to understand the relationship between circadian clock malfunction and psychiatric disease.

No MeSH data available.


Related in: MedlinePlus

The two major TTLs of the circadian molecular clock in mammals (A) and Drosophila (B). (A) The first mammalian TTL includes BMAL1 and CLK, which act as heterodimer, binding the enhancer boxes (E-boxes) in the promoter of Per and Cry clock genes. PER and CRY proteins dimerize and enter into the nucleus, where inhibit the CLK -BMAL1 activity. A second loop modulates Bmal1 expression: CLK-BMAL1 dimers induce the transcription of Rev-erbα and Ror nuclear orphan receptor genes. REV-ERBs and RORs compete for the same element (Ror-E) in the Bmal1 promoter, controlling Bmal1 transcription. Phosphorylation mediated by CKs (δ/ε) and GSK3β modulate clock protein activities regulating protein–protein interactions, nuclear translocation, and degradation. Within the master clock, at the cell level, the light stimulus induces the transcription of the Per genes via a signal transduction cascade. (B) In the first TTL of Drosophila, CLK and CYC form a dimer, which binds the E-boxes in the promoter of per and tim clock genes. PER and TIM proteins interact in a complex, enter into the nucleus, and inhibit the CLK-CYC activity. A second TTL modulates Clk expression: CLK-CYC dimer induces the transcription of vri and Pdp1 δ/ε genes. VRI and PDP1 δ/ε compete for the same element (D-box) in the Clk promoter, controlling Clk transcription. Phosphorylation mediated by DBT and SGG modulate clock protein activities, regulating protein–protein interactions, nuclear translocation, and degradation. In the cell, light activates the internal photoreceptor CRY, which associates with TIM and mediates its degradation. BMAL: brain and muscle ARNT-Like 1; CKδ: casein kinase; CLOCK: circadian locomotor output cycles Kaput; CRY: cryptochrome; CYC: cycle; DBT: doubletime; GSK3β: glycogen synthase kinase 3 beta; PDP1: PAR domain protein 1; PER: period; REV-ERB: nuclear receptor subfamily 1, group D; ROR: RAR-related orphan receptor; TIM: timeless; VRI: vrille; SGG: Shaggy. Dashed arrows indicate phosphorylation, while sinusoidal lines indicate transcription activity.
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Figure 2: The two major TTLs of the circadian molecular clock in mammals (A) and Drosophila (B). (A) The first mammalian TTL includes BMAL1 and CLK, which act as heterodimer, binding the enhancer boxes (E-boxes) in the promoter of Per and Cry clock genes. PER and CRY proteins dimerize and enter into the nucleus, where inhibit the CLK -BMAL1 activity. A second loop modulates Bmal1 expression: CLK-BMAL1 dimers induce the transcription of Rev-erbα and Ror nuclear orphan receptor genes. REV-ERBs and RORs compete for the same element (Ror-E) in the Bmal1 promoter, controlling Bmal1 transcription. Phosphorylation mediated by CKs (δ/ε) and GSK3β modulate clock protein activities regulating protein–protein interactions, nuclear translocation, and degradation. Within the master clock, at the cell level, the light stimulus induces the transcription of the Per genes via a signal transduction cascade. (B) In the first TTL of Drosophila, CLK and CYC form a dimer, which binds the E-boxes in the promoter of per and tim clock genes. PER and TIM proteins interact in a complex, enter into the nucleus, and inhibit the CLK-CYC activity. A second TTL modulates Clk expression: CLK-CYC dimer induces the transcription of vri and Pdp1 δ/ε genes. VRI and PDP1 δ/ε compete for the same element (D-box) in the Clk promoter, controlling Clk transcription. Phosphorylation mediated by DBT and SGG modulate clock protein activities, regulating protein–protein interactions, nuclear translocation, and degradation. In the cell, light activates the internal photoreceptor CRY, which associates with TIM and mediates its degradation. BMAL: brain and muscle ARNT-Like 1; CKδ: casein kinase; CLOCK: circadian locomotor output cycles Kaput; CRY: cryptochrome; CYC: cycle; DBT: doubletime; GSK3β: glycogen synthase kinase 3 beta; PDP1: PAR domain protein 1; PER: period; REV-ERB: nuclear receptor subfamily 1, group D; ROR: RAR-related orphan receptor; TIM: timeless; VRI: vrille; SGG: Shaggy. Dashed arrows indicate phosphorylation, while sinusoidal lines indicate transcription activity.

Mentions: In Drosophila, as in mammals, circadian rhythms at the molecular and cellular levels are driven by interlocking autoregulatory transcriptional/translational feedback loops (TTLs). These have been recently reviewed [e.g., Ref. (53, 54)], and here we present a simplified model of the two major TTLs (Figures 2A,B). In D. melanogaster, the transcription factors dCLOCK (dCLK) and dCYCLE (dCYC) act as a heterodimer (dCLK/dCYC), promoting the transcription of the dperiod (dper) and dtimeless (dtim) genes (Figure 2B). In mammals, the orthologs mCLK (or mNPAS2 in the forebrain) and mBMAL1 exert the function of positive regulators activating the transcription of the three mammalian orthologs of dperiod (mPer1, mPer2, and mPer3) and the two mCryptochrome genes (mCry1 and mCry2) (Figure 2A). In mammals, the mCry genes replace dtim in the main TTL. Once translated, dPER and dTIM (mPERs and mCRYs in mammals) are targeted by different kinases and phosphatases, which mediate the timing of their nuclear translocation, stability, and action as negative feedback elements of dCLK/dCYC (or mCLK/mBMAL1 in mammals) regulatory activity. Among the kinases, it is worth underlining the roles played by dSHAGGY, homologous to mammalian glycogen synthase kinase-3 (mGSK3) (55), which is involved in the phosphorylation of dTIM and dPER (mPERs and mCRYs in mammals), and by dDOUBLETIME [dDBT, homologous to mammalian Casein Kinase 1 ε (CK1ε) (56)], which targets dPER (57). These factors are involved in the regulation of dPER and dTIM (mPERs and mCRYs in mammals) stability and nuclear entry and contribute to the fine-tuning of circadian rhythmicity (58, 59) (Figures 2A,B). dCLK/dCYC (mCLK/mBMAL1) are also the positive regulators of a second TTL, which (auto)controls the rhythmic expression of dClk in flies and mBmal1 in mammals. In Drosophila, this TTL is under negative control by dVRILLE (dVRI), which probably competes with the positive regulator dPDP1 to bind sequence elements in the promoter region of dClk (60, 61) (Figure 2B). In mammals, the second TTL is controlled by the nuclear hormone receptors mRORs and mREV-ERBs, which act as transcriptional repressors and activators of mBmal1, respectively (62, 63) (Figure 2A).


Circadian Clock Dysfunction and Psychiatric Disease: Could Fruit Flies have a Say?

Zordan MA, Sandrelli F - Front Neurol (2015)

The two major TTLs of the circadian molecular clock in mammals (A) and Drosophila (B). (A) The first mammalian TTL includes BMAL1 and CLK, which act as heterodimer, binding the enhancer boxes (E-boxes) in the promoter of Per and Cry clock genes. PER and CRY proteins dimerize and enter into the nucleus, where inhibit the CLK -BMAL1 activity. A second loop modulates Bmal1 expression: CLK-BMAL1 dimers induce the transcription of Rev-erbα and Ror nuclear orphan receptor genes. REV-ERBs and RORs compete for the same element (Ror-E) in the Bmal1 promoter, controlling Bmal1 transcription. Phosphorylation mediated by CKs (δ/ε) and GSK3β modulate clock protein activities regulating protein–protein interactions, nuclear translocation, and degradation. Within the master clock, at the cell level, the light stimulus induces the transcription of the Per genes via a signal transduction cascade. (B) In the first TTL of Drosophila, CLK and CYC form a dimer, which binds the E-boxes in the promoter of per and tim clock genes. PER and TIM proteins interact in a complex, enter into the nucleus, and inhibit the CLK-CYC activity. A second TTL modulates Clk expression: CLK-CYC dimer induces the transcription of vri and Pdp1 δ/ε genes. VRI and PDP1 δ/ε compete for the same element (D-box) in the Clk promoter, controlling Clk transcription. Phosphorylation mediated by DBT and SGG modulate clock protein activities, regulating protein–protein interactions, nuclear translocation, and degradation. In the cell, light activates the internal photoreceptor CRY, which associates with TIM and mediates its degradation. BMAL: brain and muscle ARNT-Like 1; CKδ: casein kinase; CLOCK: circadian locomotor output cycles Kaput; CRY: cryptochrome; CYC: cycle; DBT: doubletime; GSK3β: glycogen synthase kinase 3 beta; PDP1: PAR domain protein 1; PER: period; REV-ERB: nuclear receptor subfamily 1, group D; ROR: RAR-related orphan receptor; TIM: timeless; VRI: vrille; SGG: Shaggy. Dashed arrows indicate phosphorylation, while sinusoidal lines indicate transcription activity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
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Figure 2: The two major TTLs of the circadian molecular clock in mammals (A) and Drosophila (B). (A) The first mammalian TTL includes BMAL1 and CLK, which act as heterodimer, binding the enhancer boxes (E-boxes) in the promoter of Per and Cry clock genes. PER and CRY proteins dimerize and enter into the nucleus, where inhibit the CLK -BMAL1 activity. A second loop modulates Bmal1 expression: CLK-BMAL1 dimers induce the transcription of Rev-erbα and Ror nuclear orphan receptor genes. REV-ERBs and RORs compete for the same element (Ror-E) in the Bmal1 promoter, controlling Bmal1 transcription. Phosphorylation mediated by CKs (δ/ε) and GSK3β modulate clock protein activities regulating protein–protein interactions, nuclear translocation, and degradation. Within the master clock, at the cell level, the light stimulus induces the transcription of the Per genes via a signal transduction cascade. (B) In the first TTL of Drosophila, CLK and CYC form a dimer, which binds the E-boxes in the promoter of per and tim clock genes. PER and TIM proteins interact in a complex, enter into the nucleus, and inhibit the CLK-CYC activity. A second TTL modulates Clk expression: CLK-CYC dimer induces the transcription of vri and Pdp1 δ/ε genes. VRI and PDP1 δ/ε compete for the same element (D-box) in the Clk promoter, controlling Clk transcription. Phosphorylation mediated by DBT and SGG modulate clock protein activities, regulating protein–protein interactions, nuclear translocation, and degradation. In the cell, light activates the internal photoreceptor CRY, which associates with TIM and mediates its degradation. BMAL: brain and muscle ARNT-Like 1; CKδ: casein kinase; CLOCK: circadian locomotor output cycles Kaput; CRY: cryptochrome; CYC: cycle; DBT: doubletime; GSK3β: glycogen synthase kinase 3 beta; PDP1: PAR domain protein 1; PER: period; REV-ERB: nuclear receptor subfamily 1, group D; ROR: RAR-related orphan receptor; TIM: timeless; VRI: vrille; SGG: Shaggy. Dashed arrows indicate phosphorylation, while sinusoidal lines indicate transcription activity.
Mentions: In Drosophila, as in mammals, circadian rhythms at the molecular and cellular levels are driven by interlocking autoregulatory transcriptional/translational feedback loops (TTLs). These have been recently reviewed [e.g., Ref. (53, 54)], and here we present a simplified model of the two major TTLs (Figures 2A,B). In D. melanogaster, the transcription factors dCLOCK (dCLK) and dCYCLE (dCYC) act as a heterodimer (dCLK/dCYC), promoting the transcription of the dperiod (dper) and dtimeless (dtim) genes (Figure 2B). In mammals, the orthologs mCLK (or mNPAS2 in the forebrain) and mBMAL1 exert the function of positive regulators activating the transcription of the three mammalian orthologs of dperiod (mPer1, mPer2, and mPer3) and the two mCryptochrome genes (mCry1 and mCry2) (Figure 2A). In mammals, the mCry genes replace dtim in the main TTL. Once translated, dPER and dTIM (mPERs and mCRYs in mammals) are targeted by different kinases and phosphatases, which mediate the timing of their nuclear translocation, stability, and action as negative feedback elements of dCLK/dCYC (or mCLK/mBMAL1 in mammals) regulatory activity. Among the kinases, it is worth underlining the roles played by dSHAGGY, homologous to mammalian glycogen synthase kinase-3 (mGSK3) (55), which is involved in the phosphorylation of dTIM and dPER (mPERs and mCRYs in mammals), and by dDOUBLETIME [dDBT, homologous to mammalian Casein Kinase 1 ε (CK1ε) (56)], which targets dPER (57). These factors are involved in the regulation of dPER and dTIM (mPERs and mCRYs in mammals) stability and nuclear entry and contribute to the fine-tuning of circadian rhythmicity (58, 59) (Figures 2A,B). dCLK/dCYC (mCLK/mBMAL1) are also the positive regulators of a second TTL, which (auto)controls the rhythmic expression of dClk in flies and mBmal1 in mammals. In Drosophila, this TTL is under negative control by dVRILLE (dVRI), which probably competes with the positive regulator dPDP1 to bind sequence elements in the promoter region of dClk (60, 61) (Figure 2B). In mammals, the second TTL is controlled by the nuclear hormone receptors mRORs and mREV-ERBs, which act as transcriptional repressors and activators of mBmal1, respectively (62, 63) (Figure 2A).

Bottom Line: Disruption of clock genes and/or the clock network might be related to the etiology of these pathologies; also, some genes, known for their circadian clock functions, might be associated to mental illnesses through clock-independent pleiotropy.There is evidence that the Drosophila brain shares some homologies with the vertebrate cerebellum, basal ganglia, and hypothalamus-pituitary-adrenal axis, the dysfunctions of which have been tied to mental illness.We sum up current knowledge on behavioral endophenotypes, which are amenable to modeling in flies, such as defects involving sleep, cognition, or social interactions, and discuss the relationship of the circadian system to these traits.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of Padova , Padova , Italy ; Cognitive Neuroscience Center, University of Padova , Padova , Italy.

ABSTRACT
There is evidence of a link between the circadian system and psychiatric diseases. Studies in humans and mammals suggest that environmental and/or genetic disruption of the circadian system leads to an increased liability to psychiatric disease. Disruption of clock genes and/or the clock network might be related to the etiology of these pathologies; also, some genes, known for their circadian clock functions, might be associated to mental illnesses through clock-independent pleiotropy. Here, we examine the features which we believe make Drosophila melanogaster a model apt to study the role of the circadian clock in psychiatric disease. Despite differences in the organization of the clock system, the molecular architecture of the Drosophila and mammalian circadian oscillators are comparable and many components are evolutionarily related. In addition, Drosophila has a rather complex nervous system, which shares much at the cell and neurobiological level with humans, i.e., a tripartite brain, the main neurotransmitter systems, and behavioral traits: circadian behavior, learning and memory, motivation, addiction, social behavior. There is evidence that the Drosophila brain shares some homologies with the vertebrate cerebellum, basal ganglia, and hypothalamus-pituitary-adrenal axis, the dysfunctions of which have been tied to mental illness. We discuss Drosophila in comparison to mammals with reference to the: organization of the brain and neurotransmitter systems; architecture of the circadian clock; clock-controlled behaviors. We sum up current knowledge on behavioral endophenotypes, which are amenable to modeling in flies, such as defects involving sleep, cognition, or social interactions, and discuss the relationship of the circadian system to these traits. Finally, we consider if Drosophila could be a valuable asset to understand the relationship between circadian clock malfunction and psychiatric disease.

No MeSH data available.


Related in: MedlinePlus