CaBP1 regulates Cav1 L-type Ca2+ channels and their coupling to neurite growth and gene transcription in mouse spiral ganglion neurons

Yang, Tian; Choi, Ji Eun; Soh, Daniel; Tobin, Kevin V.; Joiner, Mei-ling A.; Hansen, Marlan R.; Lee, Amy

doi:10.1016/j.mcn.2018.03.005

Cited by 11 publications

(17 citation statements)

References 61 publications

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“…Combined with our previous study documenting a neurite growth phenotype of auditory neurons from C-KO mice (29), the ability of NeuriteNet to sort images corresponding to DRGNs from WT and C-KO mice (Fig. 6) suggests that CaBP1 may be a general modulator of neurite growth.…”

Section: Discussionsupporting

confidence: 67%

“…We and others have established a role for CaBP1 in regulating the structural plasticity of neurites including those of spiral ganglion neurons (SGNs), which play analogous roles in hearing as DRGNs in somatosensation. In SGNs from C-KO mice, neurite regrowth is enhanced and insensitive to the inhibitory effects of depolarization (29). Thus, we hypothesized that DRGNs from C-KO mice may differ from wild-type (WT) controls in terms of their neurite growth patterns.…”

Section: Neuritenet Can Be Trained To Sort 2 Binary Variables Simultaneouslymentioning

confidence: 99%

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NeuriteNet: A Convolutional Neural Network for determining morphological differences in neurite growth

Vecchi

Mullan

Lopez

et al. 2021

Preprint

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Background: During development or regeneration, neurons extend processes (i.e., neurites) via mechanisms that can be readily analyzed in culture. However, defining the impact of a drug or genetic manipulation on such mechanisms can be challenging due to the complex arborization and heterogeneous patterns of neurite growth in vitro. New Method: NeuriteNet is a Convolutional Neural Network (CNN) sorting model that uses a novel adaptation of the XRAI saliency map overlay, which is a region-based attribution method. NeuriteNet compares neuronal populations based on differences in neurite growth patterns, sorts them into respective groups, and overlays a saliency map indicating which areas differentiated the image for the sorting procedure. Results: In this study, we demonstrate that NeuriteNet effectively sorts images corresponding to dissociated neurons into control and treatment groups according to known morphological differences. Furthermore, the saliency map overlay highlights the distinguishing features of the neuron when sorting the images into treatment groups. NeuriteNet also identifies novel morphological differences in neurites of neurons cultured from control and genetically modified mouse strains. Comparison with Existing Methods: Unlike other neurite analysis platforms, NeuriteNet does not require manual manipulations, such as segmentation of neurites prior to analysis, and is more accurate than experienced researchers for categorizing neurons according to their pattern of neurite growth. Conclusions: NeuriteNet can be used to effectively screen for morphological differences in a heterogeneous group of neurons and to provide feedback on the key features distinguishing those groups via the saliency map overlay.

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Section: Discussionsupporting

confidence: 67%

Section: Neuritenet Can Be Trained To Sort 2 Binary Variables Simultaneouslymentioning

confidence: 99%

NeuriteNet: A Convolutional Neural Network for determining morphological differences in neurite growth

Vecchi

Mullan

Lopez

et al. 2021

Preprint

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“…These findings are consistent with related studies highlighting a function for caldendrin in the hippocampus. It is required for efficient encoding of hippocampaldependent spatial and fear-based memory (Yang et al 2018a), and mice in which all CaBP1 isoforms are deleted, including caldendrin, exhibit defects in excitation/inhibition in hippocampal circuits (Nanou et al 2018;Yang et al 2018b).…”

Section: Cabp Protein Family the Physiology And Function Of Cabpsmentioning

confidence: 99%

Calcium Sensors in Neuronal Function and Dysfunction

Burgoyne

Helassa

McCue

et al. 2019

Cold Spring Harb Perspect Biol

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Calcium signaling in neurons as in other cell types can lead to varied changes in cellular function. Neuronal Ca 2+ signaling processes have also become adapted to modulate the function of specific pathways over a wide variety of time domains and these can have effects on, for example, axon outgrowth, neuronal survival, and changes in synaptic strength. Ca 2+ also plays a key role in synapses as the trigger for fast neurotransmitter release. Given its physiological importance, abnormalities in neuronal Ca 2+ signaling potentially underlie many different neurological and neurodegenerative diseases. The mechanisms by which changes in intracellular Ca 2+ concentration in neurons can bring about diverse responses is underpinned by the roles of ubiquitous or specialized neuronal Ca 2+ sensors. It has been established that synaptotagmins have key functions in neurotransmitter release, and, in addition to calmodulin, other families of EF-hand-containing neuronal Ca 2+ sensors, including the neuronal calcium sensor (NCS) and the calcium-binding protein (CaBP) families, play important physiological roles in neuronal Ca 2+ signaling. It has become increasingly apparent that these various Ca 2+ sensors may also be crucial for aspects of neuronal dysfunction and disease either indirectly or directly as a direct consequence of genetic variation or mutations. An understanding of the molecular basis for the regulation of the targets of the Ca 2+ sensors and the physiological roles of each protein in identified neurons may contribute to future approaches to the development of treatments for a variety of human neuronal disorders.C alcium signaling in many cell types can mediate a diverse range of changes in cellular function affecting gene expression, cell growth, development, survival, and cell death. In addition, neuronal calcium signaling processes have become adapted to modulate the function of other important pathways in the brain, including neuronal survival, axon outgrowth (Spitzer 2006), and changes in synaptic strength (Catterall and Few 2008;Catterall et al. 2013).Changes in the concentration of intracellular free Ca 2+ ([Ca 2+ ] i ) are essential for the transmission of information through the nervous system as the trigger for neurotransmitter release at synapses. In addition, alterations in [Ca 2+ ] i can lead to a wide variety of different physiological changes that can modify neuronal functions over a range of time domains of milliseconds through 10 sec, to minutes to days or longer (Berridge 1998). It has long been believed that

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“…Based on our previous studies of neonatal cochlear spiral ganglion neurons from caldendrin KO mice (T. Yang et al, 2018), we hypothesized that caldendrin acts as a repressor of neurite growth in sensory neurons. If so, then neurite regeneration should be enhanced in DRGNs from caldendrin KO mice as compared to those from WT mice.…”

Section: Resultsmentioning

confidence: 99%

“…Caldendrin is a member of a family of Ca 2+ binding proteins (CaBPs) that are related to calmodulin (CaM) and highly expressed in neuronal cell-types of the brain, retina, and inner ear (Haeseleer et al, 2004; Laube et al, 2002; Tippens & Lee, 2007; Yang et al, 2016). In cochlear spiral ganglion neurons, caldendrin regulates Ca v 1 channels and their coupling to the repression of neurite growth by strong depolarization (T. Yang et al, 2018). To probe the involvement of caldendrin in Ca v 1-dependent mechanisms controlling neurite regeneration, we characterized the expression of caldendrin in DRGNs and analyzed neurite growth in cultured DRGNs from wild-type (WT) and caldendrin knockout (KO) mice.…”

Section: Introductionmentioning

confidence: 99%

Caldendrin represses neurite regeneration via a sex-dependent mechanism in sensory neurons

Lopez

Yamamoto

Vecchi

et al. 2021

Preprint

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Caldendrin is a calmodulin-like Ca2+ binding protein that is expressed primarily in neurons and regulates multiple effectors including Cav1 L-type Ca2+ channels. Here, we tested the hypothesis that caldendrin regulates Cav1-dependent pathways that repress neurite growth in dorsal root ganglion neurons (DRGNs). By immunofluorescence, caldendrin was localized in medium- and large- diameter DRGNs. Consistent with an inhibitory effect of caldendrin on neurite growth, neurite initiation and growth was enhanced in dissociated DRGNs from caldendrin knockout (KO) mice compared to those from wild type (WT) mice. In an in vitro axotomy assay, caldendrin KO DRGNs grew longer neurites via a mechanism that was more sensitive to inhibitors of transcription as compared to WT DRGNs. 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. Our findings suggest that caldendrin KO mice represent an ideal model in which to interrogate the transcriptional pathways controlling neurite regeneration and how these pathways may differ in males and females.

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CaBP1 regulates Cav1 L-type Ca2+ channels and their coupling to neurite growth and gene transcription in mouse spiral ganglion neurons

Cited by 11 publications

References 61 publications

NeuriteNet: A Convolutional Neural Network for determining morphological differences in neurite growth

NeuriteNet: A Convolutional Neural Network for determining morphological differences in neurite growth

Calcium Sensors in Neuronal Function and Dysfunction

Caldendrin represses neurite regeneration via a sex-dependent mechanism in sensory neurons

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