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

2022; Oxford University Press; Volume: 50; Issue: 17 Linguagem: Inglês

10.1093/nar/gkac730

1362-4962

Robin Vuilleumier, Mo Miao, Sonia Medina-Giro, Clara-Maria Ell, Stéphane Flibotte, Tianshun Lian, Grant Kauwe, Annie Collins, Sophia Ly, George Pyrowolakis, A. Pejmun Haghighi, Douglas W. Allan,

Genetics, Aging, and Longevity in Model Organisms

Abstract 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.