Mechanistic analysis of activity-dependent BMP/TGF? release at a model synapse How do cells diversify signaling outputs of widely used intercellular signaling pathways? A handful of conserved growth factor pathways mediate communication between cells throughout life. Yet remarkably, the signaling outcomes of these pathways are finely tuned to developmental and cellular context. We will investigate signaling specificity of the BMP/TGF? pathway. This pathway serves a number of independent functions at the Drosophila NMJ. In particular, it regulates both NMJ morphological growth and neurotransmitter release. We present evidence that the cellular source of the BMP ligand Gbb discriminates between these two pathways. We propose a model in which the single-pass transmembrane protein Crimpy is a sorting receptor for the BMP for dense core vesicles in the regulated secretory pathway. We argue that (1) activity-dependent re- lease of the BMP promotes neurotransmission and (2) Crimpy defines the neuron-derived ligand pool. BMP/TGF? family members are synaptically localized and subject to activity-dependent release in mammalian neurons. However, the cellular mechanisms responsible for their localization to dense core vesicles are opaque. Crimpy would represent the first BMP/TGF? dense core vesicle sorting receptor identified in any system. Given clinical interest in identifying tools to selectively target synaptic functions of growth factor signaling pathways, a mechanistic understanding of Crimpy and its mammalian homologs will be of significant interest.

Public Health Relevance

Growth factors have diverse synaptic functions-regulating plasticity, morphology, active zone organization, neurotransmitter release, and synaptic homeostasis. We are investigating mechanisms conferring signaling specificity to the BMP/TGF? pathway at the Drosophila NMJ. We find that the BMP ligand is regulated by activity and is delivered to the presynapse by a transmembrane protein named Crimpy. We propose that Crimpy is a sorting receptor for the BMP for vesicles in the regulated secretory pathway. BMP/TGF? family members signal at synapses in many species, yet the cellular mechanisms driving this localization are unknown. As such, Crimpy would represent the first TGF/BMP sorting receptor in any species. Given clinical interest in identifying molecular handles to selectively targets synaptic functions of growth factor signaling pathways, a mechanistic understanding of Crimpy and its mammalian homologs will be of significant interest.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS084202-01
Application #
8569373
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Gubitz, Amelie
Project Start
2013-07-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$237,750
Indirect Cost
$87,750
Name
Case Western Reserve University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106