Neurexin mediates neuropeptide release from cholinergic motor neurons through dense-core vesicle localization
Abstract
Neurexins are critical synaptic cell adhesion molecules that play many roles in modulating neurotransmitter release and synaptic function, and are high-confidence risk genes for neurodevelopmental conditions such as autism. Understanding the function of the neurexin superfamily has been challenging in mammalian systems that have 3 genes ( NRXN1-3 ) that encode 2-3 major isoforms, which undergo extensive alternative splicing and generate thousands of transcripts. In contrast to mammals, C. elegans has a single gene, nrx-1 , encoding only long α and short γ isoforms. Neurexins canonically regulate synapse morphology and function in a neuron- and context-specific manner, through mechanisms related to release of chemical neurotransmitters and receptors. Whether neurexins ( nrx-1 ) impact other secretory molecules such as neuropeptides (NPs) and NP containing dense-core vesicles (DCVs) is not well understood. Here, we report that loss of nrx-1 increases the release of multiple NPs from cholinergic motor neurons in C. elegans . Using tissue specific expression and degradation of endogenous NRX-1, we find that nrx-1 functions in NP release from cholinergic neurons in a cell-autonomous manner. We confirm that loss of nrx-1 impacts cholinergic active-zone number, but also find it regulates the clustering, distribution, and expression of the DCV protein, IDA-1 (PTPRN), and the DCV secretion regulator, UNC-31 (CADPS). We find that nrx-1 functions to maintain separation and juxtaposition of neurotransmitter and NP release sites and DCV localization. Loss of cholinergic excitation ( unc-17 ) or GABAergic inhibition ( unc-25 ) did not impact cholinergic NP release, but that the increased NP release upon loss of nrx-1 is dependent on the calcium channel unc-2 . We find that neurexins can regulate NP signaling, a novel mechanism to modify circuits and behaviors, and of potential importance for NRXN1 associated human conditions.
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BibTeX
@misc{tikiyani2026neurexin,
title = {{Neurexin mediates neuropeptide release from cholinergic motor neurons through dense-core vesicle localization}},
author = {Vina Tikiyani and Michael P. Hart},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.31.748337},
url = {https://doi.org/10.64898/2026.08.31.748337},
note = {CC BY-ND 4.0},
}
RIS
TY - UNPB
TI - Neurexin mediates neuropeptide release from cholinergic motor neurons through dense-core vesicle localization
AU - Vina Tikiyani
AU - Michael P. Hart
PY - 2026
DA - 2026/08/31
PB - bioRxiv
DO - 10.64898/2026.08.31.748337
UR - https://doi.org/10.64898/2026.08.31.748337
AB - Neurexins are critical synaptic cell adhesion molecules that play many roles in modulating neurotransmitter release and synaptic function, and are high-confidence risk genes for neurodevelopmental conditions such as autism. Understanding the function of the neurexin superfamily has been challenging in mammalian systems that have 3 genes ( NRXN1-3 ) that encode 2-3 major isoforms, which undergo extensive alternative splicing and generate thousands of transcripts. In contrast to mammals, C. elegans has a single gene, nrx-1 , encoding only long α and short γ isoforms. Neurexins canonically regulate synapse morphology and function in a neuron- and context-specific manner, through mechanisms related to release of chemical neurotransmitters and receptors. Whether neurexins ( nrx-1 ) impact other secretory molecules such as neuropeptides (NPs) and NP containing dense-core vesicles (DCVs) is not well understood. Here, we report that loss of nrx-1 increases the release of multiple NPs from cholinergic motor neurons in C. elegans . Using tissue specific expression and degradation of endogenous NRX-1, we find that nrx-1 functions in NP release from cholinergic neurons in a cell-autonomous manner. We confirm that loss of nrx-1 impacts cholinergic active-zone number, but also find it regulates the clustering, distribution, and expression of the DCV protein, IDA-1 (PTPRN), and the DCV secretion regulator, UNC-31 (CADPS). We find that nrx-1 functions to maintain separation and juxtaposition of neurotransmitter and NP release sites and DCV localization. Loss of cholinergic excitation ( unc-17 ) or GABAergic inhibition ( unc-25 ) did not impact cholinergic NP release, but that the increased NP release upon loss of nrx-1 is dependent on the calcium channel unc-2 . We find that neurexins can regulate NP signaling, a novel mechanism to modify circuits and behaviors, and of potential importance for NRXN1 associated human conditions.
SN - 2692-8205
ER -