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bioRxiv · 10.1101/2022.10.28.514228

Palmitoylation regulates neuropilin-2 localization and function in cortical neurons and conveys specificity to semaphorin signaling via palmitoyl acyltransferases

Koropouli, E.·Wang, Q.·Mejias-Estevez, R.·Hand, R.·Wang, T.·Ginty, D. D.·Kolodkin, A. L.
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Abstract

Secreted semaphorin 3F (Sema3F) and semaphorin 3A (Sema3A) exhibit remarkably distinct effects on deep layer excitatory cortical pyramidal neurons; Sema3F mediates dendritic spine pruning, whereas Sema3A promotes the elaboration of basal dendrites. Sema3F and Sema3A signal through distinct holoreceptors that include neuropilin-2 (Nrp-2)/plexinA3 (PlexA3) and neuropilin-1 (Nrp-1)/PlexA4, respectively. We find that Nrp-2 and Nrp-1 are S-palmitoylated in cortical neurons and that palmitoylation of select Nrp-2 cysteines is required for its proper subcellular localization and also for Sema3F/Nrp-2-dependent dendritic spine pruning in cortical neurons, both in vitro and in vivo. Moreover, we show that the palmitoyl acyltransferase DHHC15 is required for Nrp-2 palmitoylation and Sema3F/Nrp-2-dependent dendritic spine pruning, but it is dispensable for Nrp-1 palmitoylation and Sema3A/Nrp-1-dependent basal dendritic elaboration. Therefore, palmitoyl acyltransferase-substrate specificity is essential for establishing compartmentalized neuronal structure and functional responses to extrinsic guidance cues. HIGHLIGHTSO_LINeuropilins (Nrps) are S-palmitoylated in vitro and in vivo in the central nervous system C_LIO_LIS-palmitoylation of select Nrp-2 cysteines confers subcellular localization specificity and is required for semaphorin 3F-dependent dendritic spine pruning in cortical neurons C_LIO_LIDistinct palmitoyl acyltransferases mediate Nrp-2 and Nrp-1 palmitoylation and function, imparting specificity to semaphorin signaling C_LI

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Koropouli, E., Wang, Q., Mejias-Estevez, R., Hand, R., Wang, T., Ginty, D. D., Kolodkin, A. L.. 2022-10-28. Palmitoylation regulates neuropilin-2 localization and function in cortical neurons and conveys specificity to semaphorin signaling via palmitoyl acyltransferases. https://doi.org/10.1101/2022.10.28.514228

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