Metabolic inactivation of the circadian transmitter, pigment dispersing factor (PDF), by neprilysin-like peptidases in <i>Drosophila</i>

Isaac, R. Elwyn; Johnson, Erik C.; Audsley, Neil; Shirras, Alan D.

doi:10.1242/jeb.012088

Cited by 22 publications

(20 citation statements)

References 42 publications

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“…Extracellular levels of PDF and its signaling at synapses is thought to be regulated by neuropeptidases like neprilysin. In fact, neprilysin-mediated cleavage of PDF has been shown to generate metabolites that have greatly reduced receptor-mediated signaling (Isaac et al 2007). Thus, we speculate that the lack of any corresponding effect on sleep in the Tip60 Rescue flies could be because such small increases in PDF might be regulated by endopeptidases like neprilysin.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Regulation of Axonal Growth ofDrosophilaPacemaker Cells by Histone Acetyltransferase Tip60 Controls Sleep

et al. 2012

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Tip60 is a histone acetyltransferase (HAT) enzyme that epigenetically regulates genes enriched for neuronal functions through interaction with the amyloid precursor protein (APP) intracellular domain. However, whether Tip60-mediated epigenetic dysregulation affects specific neuronal processes in vivo and contributes to neurodegeneration remains unclear. Here, we show that Tip60 HAT activity mediates axonal growth of the Drosophila pacemaker cells, termed "small ventrolateral neurons" (sLNvs), and their production of the neuropeptide pigment-dispersing factor (PDF) that functions to stabilize Drosophila sleep-wake cycles. Using genetic approaches, we show that loss of Tip60 HAT activity in the presence of the Alzheimer's disease-associated APP affects PDF expression and causes retraction of the sLNv synaptic arbor required for presynaptic release of PDF. Functional consequence of these effects is evidenced by disruption of the sleep-wake cycle in these flies. Notably, overexpression of Tip60 in conjunction with APP rescues these sleep-wake disturbances by inducing overelaboration of the sLNv synaptic terminals and increasing PDF levels, supporting a neuroprotective role for dTip60 in sLNv growth and function under APP-induced neurodegenerative conditions. Our findings reveal a novel mechanism for Tip60 mediated sleep-wake regulation via control of axonal growth and PDF levels within the sLNv-encompassing neural network and provide insight into epigenetic-based regulation of sleep disturbances observed in neurodegenerative diseases like Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

Epigenetic Regulation of Axonal Growth ofDrosophilaPacemaker Cells by Histone Acetyltransferase Tip60 Controls Sleep

et al. 2012

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“…To date, only Nep2 and Nep4 have been demonstrated to be proteolytically active (Thomas et al 2005;Bland et al 2007;Meyer et al 2009) but their in vivo targets are as yet unknown. Neprilysin-like proteins have been shown to be involved in the degradation of the insect neuropeptide pigment dispersing factor (PDF), which has been implicated in mating behavior (Isaac et al 2007); which Nep is responsible for the cleavage of PDF is unclear.…”

Section: Distribution and Potential Targets Of Neprilysins In D Melamentioning

confidence: 99%

Neprilysins: An Evolutionarily Conserved Family of Metalloproteases That Play Important Roles in Reproduction in Drosophila

et al. 2014

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Members of the M13 class of metalloproteases have been implicated in diseases and in reproductive fitness. Nevertheless, their physiological role remains poorly understood. To obtain a tractable model with which to analyze this protein family's function, we characterized the gene family in Drosophila melanogaster and focused on reproductive phenotypes. The D. melanogaster genome contains 24 M13 class protease homologs, some of which are orthologs of human proteases, including neprilysin. Many are expressed in the reproductive tracts of either sex. Using RNAi we individually targeted the five Nep genes most closely related to vertebrate neprilysin, Nep1-5, to investigate their roles in reproduction. A reduction in Nep1, Nep2, or Nep4 expression in females reduced egg laying. Nep1 and Nep2 are required in the CNS and the spermathecae for wild-type fecundity. Females that are null for Nep2 also show defects as hosts of sperm competition as well as an increased rate of depletion for stored sperm. Furthermore, eggs laid by Nep2 mutant females are fertilized normally, but arrest early in embryonic development. In the male, only Nep1 was required to induce normal patterns of female egg laying. Reduction in the expression of Nep2-5 in the male did not cause any dramatic effects on reproductive fitness, which suggests that these genes are either nonessential for male fertility or perform redundant functions. Our results suggest that, consistent with the functions of neprilysins in mammals, these proteins are also required for reproduction in Drosophila, opening up this model system for further functional analysis of this protein class and their substrates. P ROTEASES play key roles in diverse physiological systems. One such family of metalloproteases, the M13 class of neutral endopeptidases, consists mainly of membranebound zinc proteases that are involved in the processing of neuropeptides and peptide hormones (reviewed in Turner et al. 2000;Turner et al. 2001;Bland et al. 2008). In mammals, seven members of this family have been identified, of which neprilysin (NEP) and endothelin converting enzyme (ECE) are the best studied. These proteins have been implicated in various diseases including cardiovascular disease (Segura and Ruilope 2011;Wick et al. 2011), Alzheimer's disease (Mulder et al. 2012;Klein et al. 2013), inflammation and inflammatory disorders (Wong et al. 2011), and cancer (Smollich et al. 2007;Maguer-Satta et al. 2011).In addition to their role in disease, NEPs are essential for development and reproduction in mammals. The mammalian Neprilysin-2, called NL1 in mice, is highly expressed in the testis. NL1-deficient males sire fewer pups, even though spermatogenesis appears to be unaffected (Carpentier et al. 2004). In females, NEP expression in the uterus is modulated by estrogen treatment in rats (Pinto et al. 1999) and during the estrogen/progesterone cycle in humans (Head et al. 1993). In female rats and mice, controlled degradation of tachykinins, particularly substance-P, by NEP in the uterus ...

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“…Both geotactic and climbing behaviors were affected by the increased NEP2 activity. It is likely that for example PDF and tachykinin (DTK) levels are altered after NEP2 manipulations (Isaac et al 2007Isaac and Nässel 2003) and these peptides may regulate geotaxis and locomotor behavior, respectively (Mertens et al 2005;Winther et al 2006).…”

Section: Patterns Of Neuropeptide and Receptor Distribution In Drosopmentioning

confidence: 99%

Neuropeptide signaling near and far: how localized and timed is the action of neuropeptides in brain circuits?

Nässel

2009

Invert Neurosci

102

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Neuropeptide signaling is functionally very diverse and one and the same neuropeptide may act as a circulating neurohormone, as a locally released neuromodulator or even as a cotransmitter of classical fast-acting neurotransmitters. Thus, neuropeptides are produced by a huge variety of neuron types in different parts of the nervous system. Within the central nervous system (CNS) there are numerous types of peptidergic interneurons, some with strictly localized and patterned branching morphologies, others with widespread and diffuse arborizations. From morphology alone it is often difficult to predict the sphere of influence of a peptidergic interneuron, especially since it has been shown that neuropeptides can diffuse over tens of micrometers within neuropils, and that peptides probably are released exclusively in perisynaptic (or non-synaptic) regions. This review addresses some questions related to peptidergic signaling in the insect CNS. How diverse are the spatial relations between peptidergic neurons and their target neurons and what determines the sphere of functional influence? At one extreme there is volume transmission and at the other targeted cotransmission at synapses. Also temporal aspects of peptidergic signaling are of interest: how transient are peptidergic messages? Factors important for these spatial and temporal aspects of peptidergic signaling are proximity between release sites and cognate receptors, distribution of peptidase activity that can terminate peptide action and colocalization of other neuroactive compounds in the presynaptic peptidergic neuron (and corresponding receptors in target neurons). Other factors such as expression of different channel types, receptor inactivation mechanisms and second messenger systems probably also contribute to the diversity in temporal properties of peptide signaling.

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Metabolic inactivation of the circadian transmitter, pigment dispersing factor (PDF), by neprilysin-like peptidases in Drosophila

Cited by 22 publications

References 42 publications

Epigenetic Regulation of Axonal Growth ofDrosophilaPacemaker Cells by Histone Acetyltransferase Tip60 Controls Sleep

Epigenetic Regulation of Axonal Growth ofDrosophilaPacemaker Cells by Histone Acetyltransferase Tip60 Controls Sleep

Neprilysins: An Evolutionarily Conserved Family of Metalloproteases That Play Important Roles in Reproduction in Drosophila

Neuropeptide signaling near and far: how localized and timed is the action of neuropeptides in brain circuits?

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