Neuritin promotes neurite and spine growth in rat cerebellar granule cells via L‐type calcium channel‐mediated calcium influx

Abstract

Neuritin is a neurotrophic factor that is activated by neural activity and neurotrophins. Its major function is to promote neurite growth and branching; however, the underlying mechanisms are not fully understood. To address this issue, this study investigated the effects of neuritin on neurite and spine growth and intracellular Ca2+ concentration in rat cerebellar granule neurons (CGNs). Incubation of CGNs for 24 h with neuritin increased neurite length and spine density; this effect was mimicked by insulin and abolished by inhibiting insulin receptor (IR) or mitogen‐activated protein kinase kinase/extracellular signal‐regulated kinase (ERK) activity. Calcium imaging and western blot analysis revealed that neuritin enhanced the increase in intracellular Ca2+ level induced by high K+, and stimulated the cell surface expression of CaV1.2 and CaV1.3 α subunits of the L‐type calcium channel, which was suppressed by inhibition of IR or mitogen‐activated protein kinase kinase/ERK. Treatment with inhibitors of L‐type calcium channels, calmodulin, and calcineurin (CaN) abrogated the effects of neuritin on neurite length and spine density. A similar result was obtained by silencing nuclear factor of activated T cells c4, which is known to be activated by neuritin in CGNs. These results indicate that IR and ERK signaling as well as the Ca2+/CaN/nuclear factor of activated T cells c4 axis mediate the effects of neuritin on neurite and spine growth in CGNs.Open Practices Open Science: This manuscript was awarded with the Open Materials Badge.For more information see: https://cos.io/our-services/open-science-badges/ Cover Image for this issue: doi: 10.1111/jnc.14195.

Neural Stimulation and Molecular Mechanisms of Plasticity and Regeneration: A Review

“…Neuritin activity can also be mediated through nuclear factor of activated T-cells cytoplasmic 4 (NFATc4) and calcineurin (CaN). Neuritin induces neurite morphological changes through calcium signaling by upregulating L-type voltage gated calcium channels (Zhao et al, 2018 ). Additionally, the trophic factor fibroblast growth factor (FGF) appears to mediate the activity-dependent neurite morphological effects of neuritin.…”

N6-methyladenine DNA Demethylase ALKBH1 Regulates Mammalian Axon Regeneration

“…Knocking down ALKBH1 resulted in impaired sensory axon regeneration in vitro and in vivo, which could be rescued by simultaneously knocking down N6AMT1. Moreover, we observed that deleting ALKBH1 resulted in down regulation of several neurodevelopmental related genes, such as Id1 and neuritin, proteins known to regulate axon growth and regeneration (Gao et al, 2016;Huang et al, 2020;Huang et al, 2019;Lasorella et al, 2005;Sharma et al, 2015;Zhao et al, 2018). Collectively, our study not only discovered a new physiological function of ALKBH1 in neurons, but also illustrated a novel epigenetic regulatory mechanism underlying mammalian axon regeneration.…”

“…Interestingly, several of these 5 genes have been shown to regulate axon growth or regeneration. For instance, Nrn1 that encodes the protein neuritin is well known to promote axon growth and optic nerve regeneration (Gao et al, 2016;Huang et al, 2020;Sharma et al, 2015;Zhao et al, 2018). In addition, the transcription factor Id1 and its homolog Id2 have been shown to be involved in regulation of axon growth and regeneration (Huang et al, 2019;Lasorella et al, 2005).…”

ALS-FUS mutation affects the activities of HuD/ELAVL4 and FMRP leading to axon phenotypes in motoneurons

“…Given the greater changes in NRN1 levels, compared to GAP43, in FUS mutant MNs, we decided to prioritize this candidate for further analysis. Upon activation by neural activity and neurotrophins, NRN1 plays a positive role in promoting neurite outgrowth and arborization [42][43][44][45][46].…”