Circadian Period Integrates Network Information Through Activation of the BMP Signaling Pathway

Beckwith, Esteban J.; Gorostiza, Ezequiel Axel; Berni, Jimena; Rezával, Carolina; Pérez-Santángelo, Agustín; Nadra, Alejandro D.; Ceriani, M. Fernanda

doi:10.1371/journal.pbio.1001733

Cited by 21 publications

(31 citation statements)

References 75 publications

(97 reference statements)

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“…To independently regulate the pace of the clock in these cells, we activated the bone morphogenetic protein (BMP) pathway in PDF‐positive neurons. We recently showed that this manipulation inhibits dClk transcription, and therefore modulates the pace of the molecular clock (Beckwith et al, ). Thus overexpression of the nuclear BMP pathway component schnurri ( shn ) slowed down the molecular oscillator and triggered a long period phenotype of ∼1.5 hours, during which flies behaved in a perfectly rhythmic fashion (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…, middle panel). Along these lines, overexpression of constitutively active forms of the BMP pathway receptors thickveins and saxophone in PDF‐positive neurons led to a 27‐hour endogenous period with no impact on behavioral rhythmicity (Beckwith et al, ). Finally, these results constitute a previously unexplored strategy that allows the assessment of the endogenous period of non‐LNv clusters, which resulted in observations that confirm previous estimations (Yoshii et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Acceleration of the endogenous clock through overexpression of the kinase shaggy ( sgg ) was achieved with the strains uas‐ sgg WT (RRID:BDSC_11008) and uas‐ sgg CA (Martinek et al, , RRID:BDSC_5362); as an alternative strategy to speed up the clock, the doubletime ( dbt ) kinase was also employed, specifically uas‐ dbt S (Muskus et al, ). To slow down the pace of the clock, uas‐ sgg RNAi (VDRC, transformant ID 101538), and P[UAS] 756 (Beckwith et al, ), which allows shn overexpression, were used. To enhance RNAi efficiency, uas‐ dicer2 (VDRC, transformant ID 25090) was employed.…”

Section: Methodsmentioning

confidence: 99%

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Experimental assessment of the network properties of the Drosophila circadian clock

Beckwith

Ceriani

2015

J of Comparative Neurology

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Circadian rhythms are conserved across kingdoms and coordinate physiology and behavior for appropriate time-keeping. The neuronal populations that govern circadian rhythms are described in many animal models, and the current challenge is to understand how they interact to control overt rhythms, remaining plastic enough to respond and adapt to a changing environment. In Drosophila melanogaster, the circadian network comprises about 150 neurons, and the main synchronizer is the neuropeptide pigment-dispersing factor (PDF), released by the well-characterized central pacemaker neurons, the small ventral lateral neurons (sLNvs). However, the rules and properties governing the communication and coupling between this central pacemaker and downstream clusters are not fully elucidated. Here we genetically manipulate the speed of the molecular clock specifically in the central pacemaker neurons of Drosophila and provide experimental evidence of their restricted ability to synchronize downstream clusters. We also demonstrate that the sLNv-controlled clusters have an asymmetric entrainment range and were able to experimentally assess it. Our data imply that different clusters are subjected to different coupling strengths, and display independent endogenous periods. Finally, the manipulation employed here establishes a suitable paradigm to test other network properties as well as the cell-autonomous mechanisms running in different circadian-relevant clusters.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Experimental assessment of the network properties of the Drosophila circadian clock

Beckwith

Ceriani

2015

J of Comparative Neurology

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“…Wg, a well-characterized intercellular signaling molecule, is also secreted from peripheral glia associated with the fly larval neuromuscular junction to regulate the size and the organization of muscle glutamate receptor clusters (Kerr et al, 2014). Interestingly, neuronal components of BMP signaling, including Mav, also regulate the LNv clock neurons to modulate circadian period (Beckwith et al, 2013). …”

Section: Potential Circadian Glia-neuron Signaling Moleculesmentioning

confidence: 99%

Glial Cell Regulation of Rhythmic Behavior

Jackson

Sengupta

et al. 2015

Methods in Enzymology

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Brain glial cells, in particular astrocytes and microglia, secrete signaling molecules that regulate glia–glia or glia–neuron communication and synaptic activity. While much is known about roles of glial cells in nervous system development, we are only beginning to understand the physiological functions of such cells in the adult brain. Studies in vertebrate and invertebrate models, in particular mice and Drosophila, have revealed roles of glia–neuron communication in the modulation of complex behavior. This chapter emphasizes recent evidence from studies of rodents and Drosophila that highlight the importance of glial cells and similarities or differences in the neural circuits regulating circadian rhythms and sleep in the two models. The chapter discusses cellular, molecular, and genetic approaches that have been useful in these models for understanding how glia–neuron communication contributes to the regulation of rhythmic behavior.

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“…Together, these phenotypes all suggest that gbb has a broader and previously unrecognized role in the regulation of ecdysis in both larval and pupal development. Regulation of ecdysis by gbb could be related to its role in the regulation of energy homeostasis (64), which is intimately tied to the organism's ability to undergo or delay ecdysis (52), or to the role of gbb in circadian neural circuit development (65,66). With regard to the regulation of pupal ecdysis hormones, wit signaling is required specifically in CCAP neurons for CCAP expression (29).…”

Section: Functions Of Gbb In Regulation Of Ecdysis Hormones -mentioning

confidence: 99%

Alternative cleavage of a bone morphogenetic protein (BMP) produces ligands with distinct developmental functions and receptor preference

Anderson

Wharton

2017

Preprint

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TGF-β and Bone Morphogenetic Protein (BMP) family proteins are made as proprotein dimers, which are cleaved by proprotein convertases to release the active C-terminal ligand dimer. Multiple proteolytic processing sites in Glass bottom boat (Gbb), the Drosophila BMP7 ortholog, can produce distinct forms of active ligand. Cleavage at the S1 or atypical S0 site produces Gbb15, the conventional small BMP ligand, while cleavage at the NS site produces the larger Gbb38 ligand (1, 2). Here, we found that blocking NS cleavage increased association of the full length prodomain with Gbb15 resulting in a concomitant decrease in signaling activity. NS cleavage is required in vivo for Gbb-Decapentaplegic (Dpp) heterodimer-mediated wing vein patterning but not in cell culture to enable Gbb15-Dpp heterodimer activity. Gbb NS cleavage is also required in vivo for the regulation of pupal ecdysis and viability that is dependent on the type II receptor Wishful thinking (Wit). We found that the ability of Gbb38 to signal requires the expression of either Wit or the type I receptor, Saxophone (Sax). Finally, we discovered that the production of Gbb38 in 3rd instar larvae results when processing at the S1/S0 site is blocked by O-linked glycosylation. Our findings demonstrate that BMP prodomain cleavage can ensure that the mature ligand is not inhibited by the prodomain. Furthermore, alternative processing of BMP proproteins produces ligand types that signal preferentially through different receptors and exhibit specific developmental functions.Bone Morphogenetic Proteins (BMPs), members of the TGF-β family of signaling proteins, have numerous developmental and physiological roles (3)(4)(5). Like other TGF-β family members, BMPs are synthesized as large 400-500 amino acid proproteins that form dimers linked by a Cterminal disulfide (6). The 110-140 amino acid ligand domain is proteolytically cleaved from the C-terminus by a proprotein convertase (PC) such as Furin. After secretion, the C-terminally derived ligand dimer binds and activates a complex of type I and type II transmembrane serine/threonine kinase receptors. In the active complex, the type II receptor phosphorylates the type I receptor that in turn phosphorylates downstream receptor-mediated Smad (RSmad) signal transducers that act as transcription factors. While the vast majority of research in the field has focused on the activity of the ligand, there is a growing appreciation of the regulatory functions of BMP and TGF-β family prodomains (6)(7)(8). In general, it has been proposed that prodomains are important for proper folding, dimerization, and secretion of the mature ligand. A comparison of prodomains between different members of the TGF-β/BMP family shows a lower sequence conservation, in contrast to the high sequence conservation observed between their ligand domains. The low degree of prodomain sequence conservation might mean that 1 . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under aThe copyright holder...

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Circadian Period Integrates Network Information Through Activation of the BMP Signaling Pathway

Abstract: Circadian pacemaker neurons in the Drosophila brain gather network information through the highly conserved BMP signaling pathway to establish the daily period of locomotor behavior.

Cited by 21 publications

References 75 publications

Experimental assessment of the network properties of the Drosophila circadian clock

Experimental assessment of the network properties of the Drosophila circadian clock

Glial Cell Regulation of Rhythmic Behavior

Alternative cleavage of a bone morphogenetic protein (BMP) produces ligands with distinct developmental functions and receptor preference

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