Local BMP signaling: A sensor for synaptic activity that balances synapse growth and function

Vicidomini, Rosario; Serpe, Mihaela

doi:10.1016/bs.ctdb.2022.04.001

Cited by 7 publications

(8 citation statements)

References 157 publications

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“…Much of our understanding of the impact of endocytosis on BMP signaling activity has come from studies at the larval NMJ as discussed below and reviewed in ( Marqués and Zhang 2006 ; Bayat et al . 2011 ; Vicidomini and Serpe 2022 ).…”

Section: Regulation Of Bmp Signalingmentioning

confidence: 99%

“…A GluR auxiliary protein, Neto, is proposed to link the GluR clustered tetramer on the postsynaptic membrane with BMP receptors on the presynaptic membrane. Synaptic pMad appears to be a sensor of synaptic activity and has no role in regulating synaptic growth ( Vicidomini and Serpe 2022 ). It is not yet known how this pool of synaptic pMad is generated.…”

Section: Regulation Of Bmp Signalingmentioning

confidence: 99%

“…As discussed above, 3 types of BMP signaling have been revealed at the Drosophila larval NMJ: (1) canonical Gbb-induced Sax/Tkv/Wit mediates phosphorylation of Mad critical for synaptic growth, (2) local synaptic signaling involving phosphorylation of Mad by Sax/Tkv/Wit in a Gbb-independent manner, and (3) noncanonical Gbb signaling that influences LimK association with Wit, affecting actin dynamics (reviewed in Upadhyay et al . 2017 ; Vicidomini and Serpe 2022 ). For canonical signaling, the considerable physical separation of the NMJ from the nucleus requires that the intracellular signal (pMad) must be trafficked along the microtubules of the axon to the soma or cell body.…”

Section: Regulation Of Bmp Signalingmentioning

confidence: 99%

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Bone morphogenetic protein signaling: the pathway and its regulation

Akiyama,

Raftery,

Wharton

2023

Genetics

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In the mid-1960s, bone morphogenetic proteins (BMPs) were first identified in the extracts of bone to have the remarkable ability to induce heterotopic bone. When the Drosophila gene decapentaplegic (dpp) was first identified to share sequence similarity with mammalian BMP2/BMP4 in the late-1980s, it became clear that secreted BMP ligands can mediate processes other than bone formation. Following this discovery, collaborative efforts between Drosophila geneticists and mammalian biochemists made use of the strengths of their respective model systems to identify BMP signaling components and delineate the pathway. The ability to conduct genetic modifier screens in Drosophila with relative ease was critical in identifying the intracellular signal transducers for BMP signaling and the related transforming growth factor-beta/activin signaling pathway. Such screens also revealed a host of genes that encode other core signaling components and regulators of the pathway. In this review, we provide a historical account of this exciting time of gene discovery and discuss how the field has advanced over the past 30 years. We have learned that while the core BMP pathway is quite simple, composed of 3 components (ligand, receptor, and signal transducer), behind the versatility of this pathway lies multiple layers of regulation that ensures precise tissue-specific signaling output. We provide a sampling of these discoveries and highlight many questions that remain to be answered to fully understand the complexity of BMP signaling.

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Section: Regulation Of Bmp Signalingmentioning

confidence: 99%

Section: Regulation Of Bmp Signalingmentioning

confidence: 99%

Section: Regulation Of Bmp Signalingmentioning

confidence: 99%

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Bone morphogenetic protein signaling: the pathway and its regulation

Akiyama,

Raftery,

Wharton

2023

Genetics

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“…During development, the combinatorial action of various BMP ligands and receptors directs cell type-specific target gene regulation through SMAD transcription factors, but also SMADindependent functions have been described 13,15,17,19,[31][32][33][34][35][36] . In neocortical neurons, BMP2 stimulation (20 ng/ml for 45 minutes) resulted in SMAD1/5 activation in both, glutamatergic and GABAergic neurons (Extended Data Fig.…”

Section: Bmp-smad1 Signaling Controls Transcriptional Regulation Of S...mentioning

confidence: 99%

Control of neuronal excitation-inhibition balance by BMP-SMAD1 signaling

Okur

Schlauri

Bitsikas

et al. 2023

Preprint

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Throughout life, neuronal networks in the mammalian neocortex maintain a balance of excitation and inhibition which is essential for neuronal computation. Deviations from a balanced state have been linked to neurodevelopmental disorders and severe disruptions result in epilepsy. To maintain balance, neuronal microcircuits composed of excitatory and inhibitory neurons sense alterations in neural activity and adjust neuronal connectivity and function. Here, we identified a signaling pathway in the adult mouse neocortex that is activated in response to elevated neuronal network activity. Over-activation of excitatory neurons is signaled to the network through the elevation of BMP2, a growth factor well-known for its role as morphogen in embryonic development. BMP2 acts on parvalbumin-expressing (PV) interneurons through the transcription factor SMAD1, which controls an array of glutamatergic synapse proteins and components of peri-neuronal nets. PV interneuron-specific impairment of BMP2-SMAD1 signaling is accompanied by a loss of PV cell glutamatergic innervation, underdeveloped peri-neuronal nets, and decreased excitability. Ultimately, this impairment of PV interneuron functional recruitment disrupts cortical excitation-inhibition balance with mice exhibiting spontaneous epileptic seizures. Our findings suggest that developmental morphogen signaling is re-purposed to stabilize cortical networks in the adult mammalian brain.

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“…Unlike vertebrate receptors, fly NMJ iGluRs have relatively short C-terminal tails, suggesting that Neto has additional roles in receiving and transducing signals concerning synapse activity and the network status. Also, postsynaptic iGluR/Neto complexes align likely via trans-synaptic columns with the presynaptic active zone scaffold, Bruchpilot(Muttathukunnel et al 2022) and with presynaptic BMP signaling complexes(Sulkowski et al 2016;Vicidomini and Serpe 2022); through such interactions Neto can relay postsynaptic signals to presynaptic effectors that mediate presynaptic responses.The fly NMJ has been a powerful genetic model to investigate conserved mechanisms for synapse assembly, development and homeostasis. Disruption of kainate receptor biology at this synapse triggers a wide range of morphological and behavioral phenotypes, from a complete loss of postsynaptic receptors and synaptic structures, which causes embryonic paralysis and developmental lethality, to defects in the assembly and maintenance of PSDs, which generally induce locomotor deficits, and finally to subtle changes in postsynaptic composition and impairments in synaptic plasticity.…”

mentioning

confidence: 99%

Neto proteins differentially modulate the gating properties ofDrosophilaNMJ glutamate receptors

Han,

Vicidomini,

Ramos

et al. 2024

Preprint

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The formation of functional synapses requires co-assembly of ion channels with their accessory proteins which controls where, when, and how neurotransmitter receptors function. The auxiliary protein Neto modulates the function of kainate-type glutamate receptors in vertebrates as well as at the Drosophila neuromuscular junction (NMJ), a glutamatergic synapse widely used for genetic studies on synapse development. We previously reported that Neto is essential for the synaptic recruitment and function of glutamate receptors. Here, using outside-out patch-clamp recordings and fast ligand application, we examine for the first time the biophysical properties of recombinant Drosophila NMJ receptors expressed in HEK293T cells and compare them with native receptor complexes of genetically controlled composition. The two Neto isoforms, Neto-α and Neto-β, differentially modulate the gating properties of NMJ receptors. Surprisingly, we found that deactivation is extremely fast and that the decay of synaptic currents resembles the rate of iGluR desensitization. The functional analyses of recombinant iGluRs that we report here should greatly facilitate the interpretation of compound in vivo phenotypes of mutant animals.

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Local BMP signaling: A sensor for synaptic activity that balances synapse growth and function

Cited by 7 publications

References 157 publications

Bone morphogenetic protein signaling: the pathway and its regulation

Bone morphogenetic protein signaling: the pathway and its regulation

Control of neuronal excitation-inhibition balance by BMP-SMAD1 signaling

Neto proteins differentially modulate the gating properties ofDrosophilaNMJ glutamate receptors

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