17 Oral - Neurodevelopment I
Thursday April 07, 4:45 PM - 5:00 PM
Dissection of the BMP-activated synaptic gene network identifies dichotomous BMP-responsive elements regulating synaptic functions
Authors: Robin Vuilleumier 1; Mo Miao 1; Sonia Giro 1; Clara-Maria Ell 2; Stephane Flibotte 1; Tianshun Lian 1; Annie Collins 1; Sophia Ly 1; George Pyrowolakis 2; Pejmun Haghighi 3; Douglas Allan 1
Affiliations: 1) Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada.; 2) BIOSS, Centre for Biological Signaling Studies and Institute for Biology I Faculty of Biology, Albert-Ludwigs University of Freiburg, Freiburg, Germany.; 3) Buck Institute for Research on Aging, Novato, CA 94945, USA.
Keywords: m. CNS; p. cis-regulatory logic
Members of the Transforming growth factor beta (TGF-β)/Bone morphogenetic protein (BMP) family play critical roles in the regulation of synaptic growth, stability, neurotransmission, homeostasis and plasticity of several neuronal subtypes; yet how TGF-β/BMP signaling controls and coordinates these functions remains mostly unknown. Here, we uncovered a neuronal gene network, enriched for essential neurotransmission genes, that is directly controlled by retrograde BMP signaling in Drosophila motor neurons, by combining Drosophila genetics with differential RNA-seq, computational discovery of Smad-binding cis-regulatory motifs (BMP-activating elements, BMP-AE and BMP-silencer elements, BMP-SE), and reporter analysis of enhancer activity. Surprisingly, we discovered that the BMP-SE motif mediates BMP-dependent upregulation of neuronal gene transcription, similar to BMP-AEs. Exploring the underlying mechanism for this atypical activity, we found that absence in motor neurons of Shnurri (shn), a Smad transcriptional corepressor, switches the repressive function of the BMP-SE motif to an activator. This mechanism is underpinned by a lack of brinker (brk) repression by retrograde BMP signaling in motor neurons; thus brk-dependent de-repression is not a mechanism for BMP gene activation in these neurons. Finally, genome editing of identified BMP-SE and BMP-AE motifs in the loci of bruchpilot (brp) and a novel gene, without maturity (witty), showed that BMP signaling operates through these motifs to regulate synaptic maturation. Taken together, our data broaden the concept of BMP enhancer and silencer motifs, and demonstrate how the retrograde BMP signaling pathway regulates synaptic function.