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Mmp1 processing of the PDF neuropeptide regulates circadian structural plasticity of pacemaker neurons.

Depetris-Chauvin A, Fernández-Gamba A, Gorostiza EA, Herrero A, Castaño EM, Ceriani MF - PLoS Genet. (2014)

Bottom Line: Interestingly, PDF immunoreactivity at the dorsal terminals changes across the day as synaptic contacts do as a result of a remarkable remodeling of sLNv projections.However, only Mmp1 affects PDF immunoreactivity at the dorsal terminals and exerts a clear effect on overt behavior.These data demonstrate that Mmp1 modulates PDF processing, which leads to daily structural remodeling and circadian behavior.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de Genética del Comportamiento, Fundación Instituto Leloir and Instituto de Investigaciones Bioquímicas-Buenos Aires (IIB-BA, CONICET), Buenos Aires, Argentina.

ABSTRACT
In the Drosophila brain, the neuropeptide PIGMENT DISPERSING FACTOR (PDF) is expressed in the small and large Lateral ventral neurons (LNvs) and regulates circadian locomotor behavior. Interestingly, PDF immunoreactivity at the dorsal terminals changes across the day as synaptic contacts do as a result of a remarkable remodeling of sLNv projections. Despite the relevance of this phenomenon to circuit plasticity and behavior, the underlying mechanisms remain poorly understood. In this work we provide evidence that PDF along with matrix metalloproteinases (Mmp1 and 2) are key in the control of circadian structural remodeling. Adult-specific downregulation of PDF levels per se hampers circadian axonal remodeling, as it does altering Mmp1 or Mmp2 levels within PDF neurons post-developmentally. However, only Mmp1 affects PDF immunoreactivity at the dorsal terminals and exerts a clear effect on overt behavior. In vitro analysis demonstrated that PDF is hydrolyzed by Mmp1, thereby suggesting that Mmp1 could directly terminate its biological activity. These data demonstrate that Mmp1 modulates PDF processing, which leads to daily structural remodeling and circadian behavior.

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A model for the regulation of circadian axonal remodeling of sLNv neurons.The bidirectional arrow between electrical activity and Mmp1 suggests a possible coordination of both processes. Mmp1 effects on structural plasticity are dependent on the modulation of PDF levels at the sLNv terminals, via direct proteolysis, while Mmp2 appears to act downstream of the neuropeptide. Electrical activity regulates the overall level of complexity but it is not required to determine the circadian aspect of this remodeling. Given our current understanding Fas2 and EcR could act either upstream or downstream of PDF; however, the well-known Fas2 function points to a more direct modulation of circuit structure. Changes in the size of “PDF” and “Mmp1” molecules illustrate oscillations in abundance along the day.
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pgen-1004700-g006: A model for the regulation of circadian axonal remodeling of sLNv neurons.The bidirectional arrow between electrical activity and Mmp1 suggests a possible coordination of both processes. Mmp1 effects on structural plasticity are dependent on the modulation of PDF levels at the sLNv terminals, via direct proteolysis, while Mmp2 appears to act downstream of the neuropeptide. Electrical activity regulates the overall level of complexity but it is not required to determine the circadian aspect of this remodeling. Given our current understanding Fas2 and EcR could act either upstream or downstream of PDF; however, the well-known Fas2 function points to a more direct modulation of circuit structure. Changes in the size of “PDF” and “Mmp1” molecules illustrate oscillations in abundance along the day.

Mentions: In addition to the role of the molecules identified throughout this work and elsewhere [32], we previously demonstrated that adult-specific electrical silencing of PDF neurons reduces axonal complexity without abolishing circadian oscillations in their complexity, while it clamps PDF levels to the nighttime configuration [30], underscoring that although electrical activity is relevant for structural plasticity, other activity-independent mechanisms underlie axonal remodeling of the sLNv arborizations. During the early morning lLNvs show higher action potential (AP) firing rate compared to the early night [13], [62] and the limited data available on the electrophysiological properties of the sLNv neurons points in the same direction [13]; these changes in electrical properties are accompanied by high and low PDF immunoreactivity in the terminals during day and night respectively [12]. Since activity of a subset of mammalian MMPs can be modulated by electrical stimuli [63], [64], circadian changes in the electrical activity of sLNv neurons could modulate the activity of endogenous Mmps. This modulation would act in concert with the proposed clock- controlled transcriptional regulation of Mmp1 expression [29]. In this context, we propose that during the day, higher sLNv electrical activity along with low Mmp1 levels determine high PDF immunoreactivity in the axonal terminals; peptide signaling in turn promotes a more complex axonal arborization. In contrast, at night, reduced electrical activity and high Mmp1 levels result in decreased PDF immunoreactivity at the axonal terminals and this, along with the action of Mmp2, Fas2 and EcR, reduces the complexity of axonal projections (Figure 6).


Mmp1 processing of the PDF neuropeptide regulates circadian structural plasticity of pacemaker neurons.

Depetris-Chauvin A, Fernández-Gamba A, Gorostiza EA, Herrero A, Castaño EM, Ceriani MF - PLoS Genet. (2014)

A model for the regulation of circadian axonal remodeling of sLNv neurons.The bidirectional arrow between electrical activity and Mmp1 suggests a possible coordination of both processes. Mmp1 effects on structural plasticity are dependent on the modulation of PDF levels at the sLNv terminals, via direct proteolysis, while Mmp2 appears to act downstream of the neuropeptide. Electrical activity regulates the overall level of complexity but it is not required to determine the circadian aspect of this remodeling. Given our current understanding Fas2 and EcR could act either upstream or downstream of PDF; however, the well-known Fas2 function points to a more direct modulation of circuit structure. Changes in the size of “PDF” and “Mmp1” molecules illustrate oscillations in abundance along the day.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214601&req=5

pgen-1004700-g006: A model for the regulation of circadian axonal remodeling of sLNv neurons.The bidirectional arrow between electrical activity and Mmp1 suggests a possible coordination of both processes. Mmp1 effects on structural plasticity are dependent on the modulation of PDF levels at the sLNv terminals, via direct proteolysis, while Mmp2 appears to act downstream of the neuropeptide. Electrical activity regulates the overall level of complexity but it is not required to determine the circadian aspect of this remodeling. Given our current understanding Fas2 and EcR could act either upstream or downstream of PDF; however, the well-known Fas2 function points to a more direct modulation of circuit structure. Changes in the size of “PDF” and “Mmp1” molecules illustrate oscillations in abundance along the day.
Mentions: In addition to the role of the molecules identified throughout this work and elsewhere [32], we previously demonstrated that adult-specific electrical silencing of PDF neurons reduces axonal complexity without abolishing circadian oscillations in their complexity, while it clamps PDF levels to the nighttime configuration [30], underscoring that although electrical activity is relevant for structural plasticity, other activity-independent mechanisms underlie axonal remodeling of the sLNv arborizations. During the early morning lLNvs show higher action potential (AP) firing rate compared to the early night [13], [62] and the limited data available on the electrophysiological properties of the sLNv neurons points in the same direction [13]; these changes in electrical properties are accompanied by high and low PDF immunoreactivity in the terminals during day and night respectively [12]. Since activity of a subset of mammalian MMPs can be modulated by electrical stimuli [63], [64], circadian changes in the electrical activity of sLNv neurons could modulate the activity of endogenous Mmps. This modulation would act in concert with the proposed clock- controlled transcriptional regulation of Mmp1 expression [29]. In this context, we propose that during the day, higher sLNv electrical activity along with low Mmp1 levels determine high PDF immunoreactivity in the axonal terminals; peptide signaling in turn promotes a more complex axonal arborization. In contrast, at night, reduced electrical activity and high Mmp1 levels result in decreased PDF immunoreactivity at the axonal terminals and this, along with the action of Mmp2, Fas2 and EcR, reduces the complexity of axonal projections (Figure 6).

Bottom Line: Interestingly, PDF immunoreactivity at the dorsal terminals changes across the day as synaptic contacts do as a result of a remarkable remodeling of sLNv projections.However, only Mmp1 affects PDF immunoreactivity at the dorsal terminals and exerts a clear effect on overt behavior.These data demonstrate that Mmp1 modulates PDF processing, which leads to daily structural remodeling and circadian behavior.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de Genética del Comportamiento, Fundación Instituto Leloir and Instituto de Investigaciones Bioquímicas-Buenos Aires (IIB-BA, CONICET), Buenos Aires, Argentina.

ABSTRACT
In the Drosophila brain, the neuropeptide PIGMENT DISPERSING FACTOR (PDF) is expressed in the small and large Lateral ventral neurons (LNvs) and regulates circadian locomotor behavior. Interestingly, PDF immunoreactivity at the dorsal terminals changes across the day as synaptic contacts do as a result of a remarkable remodeling of sLNv projections. Despite the relevance of this phenomenon to circuit plasticity and behavior, the underlying mechanisms remain poorly understood. In this work we provide evidence that PDF along with matrix metalloproteinases (Mmp1 and 2) are key in the control of circadian structural remodeling. Adult-specific downregulation of PDF levels per se hampers circadian axonal remodeling, as it does altering Mmp1 or Mmp2 levels within PDF neurons post-developmentally. However, only Mmp1 affects PDF immunoreactivity at the dorsal terminals and exerts a clear effect on overt behavior. In vitro analysis demonstrated that PDF is hydrolyzed by Mmp1, thereby suggesting that Mmp1 could directly terminate its biological activity. These data demonstrate that Mmp1 modulates PDF processing, which leads to daily structural remodeling and circadian behavior.

Show MeSH