T-Type Calcium Channels Are Required to Maintain Viability of Neural Progenitor Cells

Oh, Hyun‐A; Lee, Sung Hoon; Kim, Ki Chan; Eun, Pyung Hwa; Ko, Mee Jung; Gonzales, Edson Luck; Seung, Hana; Kim, Seonmin; Bahn, Geon Ho; Shin, Chan Young

doi:10.4062/biomolther.2017.223

Cited by 19 publications

(26 citation statements)

References 38 publications

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“…21 Moreover, mRNA levels of Cav3.1 are higher than those of Cav3.2 in cultured rat NPC cells. 26 These observations suggest that Cav3.1 may predominantly work and contribute to the development of low-threshold calcium spikes in newly generated cells of adult mice. 23,24 In Cav3.1 KO mice, reduced proliferation and survival of newly generated cells were observed in the hippocampal SGZ.…”

Section: Discussionmentioning

confidence: 88%

“…25 Moreover, T-type calcium channels, especially Cav3.1, are expressed in rat embryo cultured neuronal progenitor cells (NPCs), and the T-type calcium channel blocker NNC 55-0396 suppresses the survival of NPCs. 26 Exposure of pregnant rats to valproic acid enhances proliferation of cultured NPCs from pups through upregulation of Cav3.1 mRNA and protein levels; this effect is blocked by NNC 55-0396. 27 These observations suggest that T-type calcium channels may be involved in adult hippocampal neurogenesis; however, their specific functions in the newly generated cells remain uncertain.…”

Section: Introductionmentioning

confidence: 99%

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Cav3.1 t‐type calcium channel is critical for cell proliferation and survival in newly generated cells of the adult hippocampus

Yabuki

Matsuo

et al. 2021

Acta Physiologica

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Aims: Adult hippocampal neurogenesis plays an important role in neuronal plasticity and maintenance in mammals. Low-threshold voltage-gated T-type calcium channels produce calcium spikes that increase fast action potentials in newborn cells in the hippocampal dentate gyrus (DG); however, their role in adult hippocampal neurogenesis remains unclear. Here, we demonstrate impaired adult hippocampal neurogenesis in Cav3.1T-type calcium channel knockout mice. Methods and Results: Cav3.1T-type calcium channel was predominantly localized in neuronal progenitor cells of the mouse hippocampal DG. By counting the number of 5-bromo-2′-deoxyuridine-labeled cells, decreased proliferation and survival of newly generated cells were observed in the adult hippocampal DG in Cav3.1 knockout mice as compared to wild-type (WT) mice. Moreover, the degree of maturation of doublecortin-positive cells in Cav3.1 knockout mice was lower than that in WT mice, suggesting that Cav3.1 deletion may impair neuronal differentiation. Consistent with impaired hippocampal neurogenesis, Cav3.1 knockout mice showed decreased social interaction. Reduced phosphorylation levels of calcium/calmodulin-dependent protein kinase II and protein kinase B were closely associated with impaired hippocampal neurogenesis in Cav3.1 knockout mice. Moreover, the mRNA and protein expression levels of brain-derived neurotrophic factor, important for neurogenesis, were significantly decreased in Cav3.1 knockout mice. Finally, gene ontology analysis revealed alterations in genes related to the promotion of cell death/apoptosis and suppression of cell proliferation/neuronal differentiation pathways, including Bdnf. Conclusion: These results suggest that the Cav3.1T-type calcium channel may be a key molecule required for cell proliferation, survival and neuronal differentiation in newly generated cells of the adult mouse hippocampus. K E Y W O R D S adult hippocampal neurogenesis, brain-derived neurotrophic factor, Cav3.1, cell proliferation, cell survival, T-type calcium channel See editorial article: Kim J-W and Shin C. Y. 2021. Deciphering the role of T-type calcium channels in regulating adult hippocampal neurogenesis. Acta Physiol (Oxf). e13643.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Cav3.1 t‐type calcium channel is critical for cell proliferation and survival in newly generated cells of the adult hippocampus

Yabuki

Matsuo

et al. 2021

Acta Physiologica

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“…Consistent with our previous in vitro findings (2), we observed a decrease in CaV3.1 expression in Purkinje cells in the present study. Because CaV3.1 appears to be required for neuroprogenitor cell viability and the primary pathway by which Ca2+ enters into cerebellar neurons (26,27), our results suggests that dyregulated calcium signaling, due to decreased CaV3.1 protein levels caused by TAF1 gene knockout, could be important in the pathogenesis of TAF1 ID syndrome.…”

Section: Cav31 T-type Channels Are Abundant At the Cerebellar Synapsmentioning

confidence: 82%

TAF1-gene editing impairs Purkinje cell morphology and function

Janakiraman

Moutal

et al. 2019

Preprint

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TAF1 intellectual disability syndrome is an X-linked disorder caused by loss-of-function mutations in the TAF1 gene. How these mutations cause dysmorphology, hypotonia, intellectual and motor defects is unknown. Mouse models which have embryonically targeted TAF1 have failed, possibly due to TAF1 being essential for viability, preferentially expressed in early brain development, and intolerant of mutation. Novel animal models are valuable tools for understanding neuronal pathology. Here, we report the development and characterization of a novel animal model for TAF1 ID syndrome in which the TAF1 gene is deleted in embryonic rats using clustered regularly interspaced short palindromic repeats (CRISPR) associated protein 9 (Cas9) technology and somatic brain transgenesis mediated by lentiviral transduction. Rat pups, post-natal day 3, were subjected to intracerebroventricular (ICV) injection of either gRNA-control or gRNA-TAF1 vectors. Rats were subjected to a battery of behavioral tests followed by histopathological analyses of brains at post-natal day 14 and day 35. TAF1-edited rats exhibited behavioral deficits at both the neonatal and juvenile stages of development. Deletion of TAF1 lead to a hypoplasia and loss of the Purkinje cells. Abnormal motor symptoms in TAF1-edited rats were associated with irregular cerebellar output caused by changes in the intrinsic activity of the Purkinje cells. Immunostaining revealed a reduction in the expression of the CaV3.1 T-type calcium channel. This animal model provides a powerful new tool for studies of neuronal dysfunction in conditions associated with TAF1 abnormalities and should prove useful for developing therapeutic strategies to treat TAF1 ID syndrome. Intellectual disability (ID) syndrome is an X-linked rare disorder caused by loss-of-function mutations in the TAF1 gene. There is no animal model for understanding neuronal pathology and to facilitate development of new therapeutics for this X-linked intellectual disability syndrome. Novel animal models are valuable tools for understanding neuronal pathology and to facilitate development of new therapeutics for diseases. Here we developed a novel animal model for TAF1 ID syndrome in which the TAF1 gene is deleted by CRISPR-Cas9 editing and lentiviral transduction. This animal model provides a powerful new tool for studies of neuronal dysfunction associated with TAF1 abnormalities and should prove useful for developing therapeutic strategies to treat TAF1 ID syndrome.

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“…Third, a T-type channel ortholog is present in motor neurons of the nematode C. elegans [36] where it contributes to motor-related functions [37,38]. Finally, a recent study documented the role of T-type channels in the maintenance of neuronal progenitor cells [39]. A loss-of-function of Ca v 3.2 could compromise the architecture of nerve cells and precipitate neuronal degeneration.…”

Section: Discussionmentioning

confidence: 99%

A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity

et al. 2020

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of cortical, brain stem and spinal motor neurons that leads to muscle weakness and death. A previous study implicated CACN A1H encoding for Ca v 3.2 calcium channels as a susceptibility gene in ALS. In the present study, two heterozygous CACNA1H variants were identified by whole genome sequencing in a small cohort of ALS patients. These variants were functionally characterized using patch clamp electrophysiology, biochemistry assays, and molecular modeling. A previously unreported c.454GTAC > G variant produced an inframe deletion of a highly conserved isoleucine residue in Ca v 3.2 (p.ΔI153) and caused a complete loss-of-function of the channel, with an additional dominantnegative effect on the wild-type channel when expressed in trans. In contrast, the c.3629C > T variant caused a missense substitution of a proline with a leucine (p.P1210L) and produced a comparatively mild alteration of Ca v 3.2 channel activity. The newly identified ΔI153 variant is the first to be reported to cause a complete loss of Ca v 3.2 channel function. These findings add to the notion that loss-of-function of Ca v 3.2 channels associated with rare CACNA1H variants may be risk factors in the complex etiology of ALS.

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T-Type Calcium Channels Are Required to Maintain Viability of Neural Progenitor Cells

Cited by 19 publications

References 38 publications

Cav3.1 t‐type calcium channel is critical for cell proliferation and survival in newly generated cells of the adult hippocampus

Cav3.1 t‐type calcium channel is critical for cell proliferation and survival in newly generated cells of the adult hippocampus

TAF1-gene editing impairs Purkinje cell morphology and function

A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity

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