The Calcium Channel Subunit α<sub>2</sub>δ-3 Promotes Activity-Dependent, Autocrine BMP Signaling to Organize Presynaptic Terminals

Bibliographic Details
Main Author:	Hoover, Kendall
Language:	English
Published:	Case Western Reserve University School of Graduate Studies / OhioLINK 2020
Subjects:	Neurosciences
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=case1575636483960192

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spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-case15756364839601922021-08-03T07:13:36Z The Calcium Channel Subunit α<sub>2</sub>δ-3 Promotes Activity-Dependent, Autocrine BMP Signaling to Organize Presynaptic Terminals Hoover, Kendall Neurosciences <p>Activity-dependent signaling pathways are crucial to synapse development and function, and defects in these pathways result in neurodegeneration, depression, among other developmental disorders. The conserved bone morphogenetic protein (BMP) pathway, directs NMJ growth and neurotransmitter release at the <i>Drosophila melanogaster</i> neuromuscular junction (NMJ). Tissue-specific rescue experiments have demonstrated that distinct pools of the BMP ligand Glass bottom boat (Gbb) control NMJ morphology and function. While postsynaptic Gbb promotes overall NMJ growth, presynaptic Gbb promotes neurotransmission. Excitingly, our lab was able to identify the presynaptic pool, yet the precise role of presynaptic Gbb in regulating synaptic function remains unknown. </p><p>Here we show the role of the activity-dependent Gbb signal in synaptic assembly and function. We found that presynaptic Gbb loss of function mutants exhibit defects in active zone architecture, synaptic vesicle distribution, and transmission. Loss of either the BMP type II receptor Wit or the transcription factor Mad results in analogous phenotypes, arguing for a canonical BMP pathway. Moreover, defects in <i>wit</i> mutants are rescued by neuronal expression of Wit, advocating for an autocrine BMP pathway. We further demonstrate that continuous expression of presynaptic Gbb is required for synapse structure, temporally separating this presynaptic cue from the early pro-growth signal.</p><p>Interestingly, embryonic bouton morphogenesis is suspended in BMP mutants, a phenotype akin to that observed in mutants lacking α<sub>2</sub>δ-3, an auxiliary calcium channel subunit required for trafficking and localization of the pore-forming subunit. Upon further investigation of the <i> α<sub>2</sub>δ-3 </i> mutants later in development, we discovered similar synaptic defects, hinting that there may be related functions for BMP signaling and α<sub>2</sub>δ-3 in presynaptic organization. In fact, overexpression of Gbb in motor neurons suppressed structural and behavioral phenotypes observed in <i> α<sub>2</sub>δ-3 </i> mutants, suggesting these deficits result from reduced Gbb signaling. </p><p>Given that α<sub>2</sub>δ-3 is completely extracellular, we hypothesized that it could be acting as a physical barrier to Gbb diffusion after being released from the presynaptic terminal. Indeed, we found that the α<sub>2</sub> peptide of α<sub>2</sub>δ-3 promotes Gbb distribution proximal to the presynaptic membrane following neuronal stimulation, showing that α<sub>2</sub>δ-3 is an important scaffold within the synaptic cleft microenvironment. Collectively, we reason that activity-dependent, autocrine signaling pathways provide neurons with continuous feedback and play a significant role in directing proper synapse structure and function. </p> 2020-01-28 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1575636483960192 http://rave.ohiolink.edu/etdc/view?acc_num=case1575636483960192 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection	NDLTD
language	English
sources	NDLTD
topic	Neurosciences
spellingShingle	Neurosciences Hoover, Kendall The Calcium Channel Subunit α<sub>2</sub>δ-3 Promotes Activity-Dependent, Autocrine BMP Signaling to Organize Presynaptic Terminals
author	Hoover, Kendall
author_facet	Hoover, Kendall
author_sort	Hoover, Kendall
title	The Calcium Channel Subunit α<sub>2</sub>δ-3 Promotes Activity-Dependent, Autocrine BMP Signaling to Organize Presynaptic Terminals
title_short	The Calcium Channel Subunit α<sub>2</sub>δ-3 Promotes Activity-Dependent, Autocrine BMP Signaling to Organize Presynaptic Terminals
title_full	The Calcium Channel Subunit α<sub>2</sub>δ-3 Promotes Activity-Dependent, Autocrine BMP Signaling to Organize Presynaptic Terminals
title_fullStr	The Calcium Channel Subunit α<sub>2</sub>δ-3 Promotes Activity-Dependent, Autocrine BMP Signaling to Organize Presynaptic Terminals
title_full_unstemmed	The Calcium Channel Subunit α<sub>2</sub>δ-3 Promotes Activity-Dependent, Autocrine BMP Signaling to Organize Presynaptic Terminals
title_sort	calcium channel subunit α<sub>2</sub>δ-3 promotes activity-dependent, autocrine bmp signaling to organize presynaptic terminals
publisher	Case Western Reserve University School of Graduate Studies / OhioLINK
publishDate	2020
url	http://rave.ohiolink.edu/etdc/view?acc_num=case1575636483960192
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The Calcium Channel Subunit α<sub>2</sub>δ-3 Promotes Activity-Dependent, Autocrine BMP Signaling to Organize Presynaptic Terminals

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