Caldendrin represses neurite regeneration and growth in dorsal root ganglion neurons

Abstract

Caldendrin is a Ca2+ binding protein that interacts with multiple effectors, such as the Cav1 L-type Ca2+ channel, which play a prominent role in regulating the outgrowth of dendrites and axons (i.e., neurites) during development and in response to injury. Here, we investigated the role of caldendrin in Cav1-dependent pathways that impinge upon neurite growth in dorsal root ganglion neurons (DRGNs). By immunofluorescence, caldendrin was localized in medium- and large- diameter DRGNs. Compared to DRGNs cultured from WT mice, DRGNs of caldendrin knockout (KO) mice exhibited enhanced neurite regeneration and outgrowth. Strong depolarization, which normally represses neurite growth through activation of Cav1 channels, had no effect on neurite growth in DRGN cultures from female caldendrin KO mice. Remarkably, DRGNs from caldendrin KO males were no different from those of WT males in terms of depolarization-dependent neurite growth repression. We conclude that caldendrin opposes neurite regeneration and growth, and this involves coupling of Cav1 channels to growth-inhibitory pathways in DRGNs of females but not males.

Caldendrin Is a Repressor of PIEZO2 Channels and Touch Sensation in Mice

“…To gain insights into the somatosensory function of caldendrin, we analyzed the expression of CaBP1 in specific classes of DRGNs using a single cell (sc)RNA-seq dataset (GSE154659) described previously ( Renthal et al, 2020 ). We previously showed that most (∼92%) of DRGNs that express caldendrin also express neurofilament 200 (NF200) ( Lopez et al, 2023 )—a marker of mechanically sensitive DRGNs that includes A-b LTMRs, A-d LTMRs, and proprioceptors ( Kupari et al, 2021 ). Consistent with these findings, the scRNAseq analysis indicated highest expression of Cabp1 mRNA in DRGNs that express NF200 mRNA.…”

“…Current densities within each DRGN subclass were more variable in Cabp1 KO than in WT mice, which could reflect the differences in caldendrin expression between DRGN subtypes based on the RNAseq and immunofluorescence analyses ( Fig. 1 ; Lopez et al, 2023 ). There was no significant difference in the percentage of DRGNs in each category ( Fig.…”

“…6 F ) and so could neutralize the impact of caldendrin-L on inactivation in DRGNs where both variants are expressed ( Fig. 4 B ; Lopez et al, 2023 ). In addition, N2A cells exhibit properties of transformed cells and may not fully recapitulate the cellular context of DRGNs.…”

“…Like CaM, caldendrin/CaBP1 bind to a variety of ion channels and, in some cases, antagonize the effects of CaM on channel function ( Zhou et al, 2004 ; Kinoshita-Kawada et al, 2005 ; Tippens and Lee, 2007 ; Findeisen et al, 2013 ; Li et al, 2013 ). Unlike CaM, caldendrin is expressed primarily in neuronal cell types ( Kim et al, 2014 ) and is particularly abundant in sensory neurons in the inner ear and DRG ( Yang et al, 2016 ; Lopez et al, 2023 ). Caldendrin is the main Cabp1 splice variant expressed within the DRG and is highly expressed in large myelinated DRGNs ( Lopez et al, 2023 ), which are involved in transmitting information about innocuous touch ( Abraira and Ginty, 2013 ).…”

“…Unlike CaM, caldendrin is expressed primarily in neuronal cell types ( Kim et al, 2014 ) and is particularly abundant in sensory neurons in the inner ear and DRG ( Yang et al, 2016 ; Lopez et al, 2023 ). Caldendrin is the main Cabp1 splice variant expressed within the DRG and is highly expressed in large myelinated DRGNs ( Lopez et al, 2023 ), which are involved in transmitting information about innocuous touch ( Abraira and Ginty, 2013 ). To test the hypothesis that caldendrin regulates the properties of MA channels in DRGNs and their involvement in touch sensation, we used global and conditional Cabp1 knock-out (KO) mouse strains in concert with electrophysiological, behavioral, and biochemical strategies.…”