A PDZ-RapGEF promotes synaptic development in Caenorhabditis elegans through a Rap/Rac signaling pathway

Reagan Lamb; Michael Scales; Julie Watkins; Martin Werner; Salvatore J. Cherra

doi:10.1242/dev.204678

A PDZ-RapGEF promotes synaptic development in Caenorhabditis elegans through a Rap/Rac signaling pathway

Reagan Lamb, Michael Scales, Julie Watkins, Martin Werner, Salvatore J. Cherra

Research output: Contribution to journal › Article › peer-review

Abstract

Small G proteins coordinate the development of nerve terminals. The activity of G proteins is finely tuned by GTPase regulatory proteins. Previously, we have observed that PXF-1, a Caenorhabditis elegans GTPase regulatory protein, is required for the function of cholinergic motor neurons. Here, we investigated how PXF-1 coordinates the development of presynaptic terminals at the molecular level. We observed that PXF-1 acts through RAP-1 to promote synapse development. Subsequently, we found that pxf-1 mutants display a reduction in RAC-2 activity, which is required for cholinergic synapse development. We observed that RAC-2 acts downstream of RAP-1. Finally, we identified a physical interaction between RAP-1 and TIAM-1, a Rac guanine exchange factor, which links PXF-1 function to the presynaptic actin cytoskeleton through RAC-2 activation. These findings highlight how small G protein signaling pathways interact to coordinate the development of presynaptic terminals.

Original language	English
Article number	dev204678
Journal	Development (Cambridge)
Volume	152
Issue number	16
DOIs	https://doi.org/10.1242/dev.204678
State	Published - Aug 2025

Bibliographical note

Publisher Copyright:
© 2025. Published by The Company of Biologists.

Funding

We thank Avanti Sawardekar and Bithika Dhar for the creation of reagents and initial validation of rap-1 and rac-2 cDNA expression. FRET-FLIM image acquisition and data analysis were performed using resources at the Light Microscopy Core at the University of Kentucky. Some mutant strains were provided by the Caenorhabditis Genetics Center, which is supported by the NIH (OD010440). This research was supported in part by grants from the National Institute of Neurological Disorders and Stroke (NS097638 and NS129668-01A1 to S.J.C., NS129159-01A1 to R.L.). Open Access funding provided by University of Kentucky. Deposited in PMC for immediate release. This research was supported in part by grants from the National Institute of Neurological Disorders and Stroke (NS097638 and NS129668-01A1 to S.J.C., NS129159-01A1 to R.L.). Open Access funding provided by University of Kentucky. Deposited in PMC for immediate release. We thank Avanti Sawardekar and Bithika Dhar for the creation of reagents and initial validation of rap-1 and rac-2 cDNA expression. FRET-FLIM image acquisition and data analysis were performed using resources at the Light Microscopy Core at the University of Kentucky. Some mutant strains were provided by the Caenorhabditis Genetics Center, which is supported by the NIH (OD010440).

Funders	Funder number
University of Kentucky
Population Media Center
National Institutes of Health (NIH)	OD010440
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council	NS097638, NS129159-01A1, NS129668-01A1

Keywords

FRET-FLIM
G proteins
Neuromuscular junction
RapGEF
Synaptic vesicles

ASJC Scopus subject areas

Molecular Biology
Developmental Biology

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10.1242/dev.204678

Cite this

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title = "A PDZ-RapGEF promotes synaptic development in Caenorhabditis elegans through a Rap/Rac signaling pathway",

abstract = "Small G proteins coordinate the development of nerve terminals. The activity of G proteins is finely tuned by GTPase regulatory proteins. Previously, we have observed that PXF-1, a Caenorhabditis elegans GTPase regulatory protein, is required for the function of cholinergic motor neurons. Here, we investigated how PXF-1 coordinates the development of presynaptic terminals at the molecular level. We observed that PXF-1 acts through RAP-1 to promote synapse development. Subsequently, we found that pxf-1 mutants display a reduction in RAC-2 activity, which is required for cholinergic synapse development. We observed that RAC-2 acts downstream of RAP-1. Finally, we identified a physical interaction between RAP-1 and TIAM-1, a Rac guanine exchange factor, which links PXF-1 function to the presynaptic actin cytoskeleton through RAC-2 activation. These findings highlight how small G protein signaling pathways interact to coordinate the development of presynaptic terminals.",

keywords = "FRET-FLIM, G proteins, Neuromuscular junction, RapGEF, Synaptic vesicles",

author = "Reagan Lamb and Michael Scales and Julie Watkins and Martin Werner and Cherra, \{Salvatore J.\}",

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doi = "10.1242/dev.204678",

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AU - Lamb, Reagan

AU - Scales, Michael

AU - Watkins, Julie

AU - Werner, Martin

AU - Cherra, Salvatore J.

PY - 2025/8

Y1 - 2025/8

N2 - Small G proteins coordinate the development of nerve terminals. The activity of G proteins is finely tuned by GTPase regulatory proteins. Previously, we have observed that PXF-1, a Caenorhabditis elegans GTPase regulatory protein, is required for the function of cholinergic motor neurons. Here, we investigated how PXF-1 coordinates the development of presynaptic terminals at the molecular level. We observed that PXF-1 acts through RAP-1 to promote synapse development. Subsequently, we found that pxf-1 mutants display a reduction in RAC-2 activity, which is required for cholinergic synapse development. We observed that RAC-2 acts downstream of RAP-1. Finally, we identified a physical interaction between RAP-1 and TIAM-1, a Rac guanine exchange factor, which links PXF-1 function to the presynaptic actin cytoskeleton through RAC-2 activation. These findings highlight how small G protein signaling pathways interact to coordinate the development of presynaptic terminals.

AB - Small G proteins coordinate the development of nerve terminals. The activity of G proteins is finely tuned by GTPase regulatory proteins. Previously, we have observed that PXF-1, a Caenorhabditis elegans GTPase regulatory protein, is required for the function of cholinergic motor neurons. Here, we investigated how PXF-1 coordinates the development of presynaptic terminals at the molecular level. We observed that PXF-1 acts through RAP-1 to promote synapse development. Subsequently, we found that pxf-1 mutants display a reduction in RAC-2 activity, which is required for cholinergic synapse development. We observed that RAC-2 acts downstream of RAP-1. Finally, we identified a physical interaction between RAP-1 and TIAM-1, a Rac guanine exchange factor, which links PXF-1 function to the presynaptic actin cytoskeleton through RAC-2 activation. These findings highlight how small G protein signaling pathways interact to coordinate the development of presynaptic terminals.

KW - FRET-FLIM

KW - G proteins

KW - Neuromuscular junction

KW - RapGEF

KW - Synaptic vesicles

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ER -

A PDZ-RapGEF promotes synaptic development in Caenorhabditis elegans through a Rap/Rac signaling pathway

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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