Glia-neuron signaling mediated by two different BMP ligands impacts synaptic growth

Abstract

The nervous system is a complex network of cells whose interactions provide circuitry necessary for an organism to perceive and move through its environment. Revealing the molecular basis of how neurons and non-neuronal glia communicate is essential for understanding neural development, behavior, and abnormalities of the nervous system. BMP signaling in motor neurons, activated in part by retrograde signals from muscle expressed Gbb (BMP5/6/7) has been implicated in synaptic growth, function and plasticity in Drosophila melanogaster. Through loss-of-function studies, we establish Gbb as a critical mediator of glia to neuron signaling important for proper synaptic growth. Furthermore, the BMP2/4 ortholog, Dpp, expressed in a subset of motor neurons, acts by autocrine signaling to also facilitate neuromuscular junction (NMJ) growth at specific muscle innervation sites. In addition to signaling from glia to motor neurons, autocrine Gbb induces signaling in larval VNC glia which strongly express the BMP type II receptor, Wit. In addition, to Dpps autocrine motor neuron signaling, Dpp also engages in paracrine signaling, to adjacent glia but not to neighboring motor neurons. In one type of dorsal midline motor neuron, RP2, dpp transcription is under tight regulation, as its expression is under autoregulatory control in RP2 but not aCC neurons. Taken together our findings indicate that bi-directional BMP signaling, mediated by two different ligands, facilitates communication between glia and neurons. Gbb, prominently expressed in glia, and Dpp acting from a discrete set of neurons induce active Smad-dependent BMP signaling to influence bouton number during neuromuscular junction growth.

BMP/TGF‐β signaling as a modulator of neurodegeneration in ALS

“…In the Drosophila nervous system, pMad‐dependent BMP signaling is activated in multiple cell types: muscles, motor neurons, and glia. The BMP5/6/7 ortholog, gbb , and the BMP2/4 ortholog, dpp , are each expressed by distinct sets of cells, and contribute differentially to the activation of signaling in target cells 145,146 . This kind of spatial difference in ligand production will be first regulated at the level of gene transcription, then by dimer formation, proprotein processing, post‐translational modifications during trafficking, and secretion 110,147 .…”

“…The BMP5/6/7 ortholog, gbb, and the BMP2/4 ortholog, dpp, are each expressed by distinct sets of cells, and contribute differentially to the activation of signaling in target cells. 145,146 This kind of spatial difference in ligand production will be first regulated at the level of gene transcription, then by dimer formation, proprotein processing, post-translational modifications during trafficking, and secretion. 110,147 As such, in addition to BMP ligand maturation, their structural properties, and availability for receptor binding are also known to alter signaling output, 148,149 as demonstrated by the requirement for a specific Gbb proprotein proconvertase processing event that impacts CCAP (crustacean cardioactive peptide) neuropeptide production in CNS neurons.…”