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Dichotomous cis-regulatory motifs mediate the maturation of the neuromuscular junction by retrograde BMP signaling

Retrograde bone morphogenetic protein (BMP) signaling at the Drosophila neuromuscular junction (NMJ) has served as a paradigm to study TGF-β-dependent synaptic function and maturation. Yet, how retrograde BMP signaling transcriptionally regulates these functions remains unresolved. Here, we uncover...

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Autores principales: Vuilleumier, Robin, Miao, Mo, Medina-Giro, Sonia, Ell, Clara-Maria, Flibotte, Stephane, Lian, Tianshun, Kauwe, Grant, Collins, Annie, Ly, Sophia, Pyrowolakis, George, Haghighi, A Pejmun, Allan, Douglas W
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9508838/
https://www.ncbi.nlm.nih.gov/pubmed/36029115
http://dx.doi.org/10.1093/nar/gkac730
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author Vuilleumier, Robin
Miao, Mo
Medina-Giro, Sonia
Ell, Clara-Maria
Flibotte, Stephane
Lian, Tianshun
Kauwe, Grant
Collins, Annie
Ly, Sophia
Pyrowolakis, George
Haghighi, A Pejmun
Allan, Douglas W
author_facet Vuilleumier, Robin
Miao, Mo
Medina-Giro, Sonia
Ell, Clara-Maria
Flibotte, Stephane
Lian, Tianshun
Kauwe, Grant
Collins, Annie
Ly, Sophia
Pyrowolakis, George
Haghighi, A Pejmun
Allan, Douglas W
author_sort Vuilleumier, Robin
collection PubMed
description Retrograde bone morphogenetic protein (BMP) signaling at the Drosophila neuromuscular junction (NMJ) has served as a paradigm to study TGF-β-dependent synaptic function and maturation. Yet, how retrograde BMP signaling transcriptionally regulates these functions remains unresolved. Here, we uncover a gene network, enriched for neurotransmission-related genes, that is controlled by retrograde BMP signaling in motor neurons through two Smad-binding cis-regulatory motifs, the BMP-activating (BMP-AE) and silencer (BMP-SE) elements. Unpredictably, both motifs mediate direct gene activation, with no involvement of the BMP derepression pathway regulators Schnurri and Brinker. Genome editing of candidate BMP-SE and BMP-AE within the locus of the active zone gene bruchpilot, and a novel Ly6 gene witty, demonstrated the role of these motifs in upregulating genes required for the maturation of pre- and post-synaptic NMJ compartments. Our findings uncover how Smad-dependent transcriptional mechanisms specific to motor neurons directly orchestrate a gene network required for synaptic maturation by retrograde BMP signaling.
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spelling pubmed-95088382022-09-26 Dichotomous cis-regulatory motifs mediate the maturation of the neuromuscular junction by retrograde BMP signaling Vuilleumier, Robin Miao, Mo Medina-Giro, Sonia Ell, Clara-Maria Flibotte, Stephane Lian, Tianshun Kauwe, Grant Collins, Annie Ly, Sophia Pyrowolakis, George Haghighi, A Pejmun Allan, Douglas W Nucleic Acids Res Gene regulation, Chromatin and Epigenetics Retrograde bone morphogenetic protein (BMP) signaling at the Drosophila neuromuscular junction (NMJ) has served as a paradigm to study TGF-β-dependent synaptic function and maturation. Yet, how retrograde BMP signaling transcriptionally regulates these functions remains unresolved. Here, we uncover a gene network, enriched for neurotransmission-related genes, that is controlled by retrograde BMP signaling in motor neurons through two Smad-binding cis-regulatory motifs, the BMP-activating (BMP-AE) and silencer (BMP-SE) elements. Unpredictably, both motifs mediate direct gene activation, with no involvement of the BMP derepression pathway regulators Schnurri and Brinker. Genome editing of candidate BMP-SE and BMP-AE within the locus of the active zone gene bruchpilot, and a novel Ly6 gene witty, demonstrated the role of these motifs in upregulating genes required for the maturation of pre- and post-synaptic NMJ compartments. Our findings uncover how Smad-dependent transcriptional mechanisms specific to motor neurons directly orchestrate a gene network required for synaptic maturation by retrograde BMP signaling. Oxford University Press 2022-08-27 /pmc/articles/PMC9508838/ /pubmed/36029115 http://dx.doi.org/10.1093/nar/gkac730 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Gene regulation, Chromatin and Epigenetics
Vuilleumier, Robin
Miao, Mo
Medina-Giro, Sonia
Ell, Clara-Maria
Flibotte, Stephane
Lian, Tianshun
Kauwe, Grant
Collins, Annie
Ly, Sophia
Pyrowolakis, George
Haghighi, A Pejmun
Allan, Douglas W
Dichotomous cis-regulatory motifs mediate the maturation of the neuromuscular junction by retrograde BMP signaling
title Dichotomous cis-regulatory motifs mediate the maturation of the neuromuscular junction by retrograde BMP signaling
title_full Dichotomous cis-regulatory motifs mediate the maturation of the neuromuscular junction by retrograde BMP signaling
title_fullStr Dichotomous cis-regulatory motifs mediate the maturation of the neuromuscular junction by retrograde BMP signaling
title_full_unstemmed Dichotomous cis-regulatory motifs mediate the maturation of the neuromuscular junction by retrograde BMP signaling
title_short Dichotomous cis-regulatory motifs mediate the maturation of the neuromuscular junction by retrograde BMP signaling
title_sort dichotomous cis-regulatory motifs mediate the maturation of the neuromuscular junction by retrograde bmp signaling
topic Gene regulation, Chromatin and Epigenetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9508838/
https://www.ncbi.nlm.nih.gov/pubmed/36029115
http://dx.doi.org/10.1093/nar/gkac730
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