Store-operated CRAC channels regulate gene expression and proliferation in neural progenitor cells

doi:10.1523/JNEUROSCI.0263-14.2014

. 2014 Jul 2;34(27):9107-23.

doi: 10.1523/JNEUROSCI.0263-14.2014.

Store-operated CRAC channels regulate gene expression and proliferation in neural progenitor cells

Agila Somasundaram¹, Andrew K Shum¹, Helen J McBride², John A Kessler³, Stefan Feske⁴, Richard J Miller¹, Murali Prakriya⁵

Affiliations

¹ Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.
² Department of Discovery Toxicology, Amgen, Inc., Thousand Oaks, California 91320.
³ Department of Neurology, Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, and.
⁴ Department of Pathology, New York University Langone Medical Center, New York, New York 10016.
⁵ Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, m-prakriya@northwestern.edu.

PMID: 24990931
PMCID: PMC4078087
DOI: 10.1523/JNEUROSCI.0263-14.2014

Store-operated CRAC channels regulate gene expression and proliferation in neural progenitor cells

Agila Somasundaram et al. J Neurosci. 2014.

. 2014 Jul 2;34(27):9107-23.

doi: 10.1523/JNEUROSCI.0263-14.2014.

Authors

Agila Somasundaram¹, Andrew K Shum¹, Helen J McBride², John A Kessler³, Stefan Feske⁴, Richard J Miller¹, Murali Prakriya⁵

Affiliations

¹ Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.
² Department of Discovery Toxicology, Amgen, Inc., Thousand Oaks, California 91320.
³ Department of Neurology, Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, and.
⁴ Department of Pathology, New York University Langone Medical Center, New York, New York 10016.
⁵ Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, m-prakriya@northwestern.edu.

PMID: 24990931
PMCID: PMC4078087
DOI: 10.1523/JNEUROSCI.0263-14.2014

Abstract

Calcium signals regulate many critical processes during vertebrate brain development including neurogenesis, neurotransmitter specification, and axonal outgrowth. However, the identity of the ion channels mediating Ca(2+) signaling in the developing nervous system is not well defined. Here, we report that embryonic and adult mouse neural stem/progenitor cells (NSCs/NPCs) exhibit store-operated Ca(2+) entry (SOCE) mediated by Ca(2+) release-activated Ca(2+) (CRAC) channels. SOCE in NPCs was blocked by the CRAC channel inhibitors La(3+), BTP2, and 2-APB and Western blots revealed the presence of the canonical CRAC channel proteins STIM1 and Orai1. Knock down of STIM1 or Orai1 significantly diminished SOCE in NPCs, and SOCE was lost in NPCs from transgenic mice lacking Orai1 or STIM1 and in knock-in mice expressing the loss-of-function Orai1 mutant, R93W. Therefore, STIM1 and Orai1 make essential contributions to SOCE in NPCs. SOCE in NPCs was activated by epidermal growth factor and acetylcholine, the latter occurring through muscarinic receptors. Activation of SOCE stimulated gene transcription through calcineurin/NFAT (nuclear factor of activated T cells) signaling through a mechanism consistent with local Ca(2+) signaling by Ca(2+) microdomains near CRAC channels. Importantly, suppression or deletion of STIM1 and Orai1 expression significantly attenuated proliferation of embryonic and adult NPCs cultured as neurospheres and, in vivo, in the subventricular zone of adult mice. These findings show that CRAC channels serve as a major route of Ca(2+) entry in NPCs and regulate key effector functions including gene expression and proliferation, indicating that CRAC channels are important regulators of mammalian neurogenesis.

Keywords: CRAC channels; Orai1; STIM1; calcium; progenitor cell; proliferation.

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Figures

**Figure 1.**
Mouse NPCs exhibit SOCE with pharmacological properties consistent with CRAC channels. A, Depletion of ER Ca²⁺ stores evokes La³⁺-sensitive SOCE. ER Ca²⁺ stores were depleted with 1 μm TG in a Ca²⁺-free Ringer's solution and extracellular Ca²⁺ was re-added to evoke SOCE. SOCE is blocked by 2 μm LaCl₃ (E18; ***p < 0.001 by 2-tailed unpaired t test; n = 80 cells; representative of experiments from 4 cultures of NPCs cultured from E18 embryos). B, The CRAC channel modulator 2-APB (10 μm) produces dual effects on SOCE in NPCs. Administration of 2-APB caused transient potentiation, followed by inhibition, as described previously for CRAC channels (Prakriya and Lewis, 2001; E13, **p < 0.01, 2-tailed unpaired t test; n = 14 cells, representative of 3 cultures of E13 NPCs). C, The CRAC channel inhibitor BTP-2 attenuated SOCE in NPCs. NPCs were pretreated with BTP-2 (1 μm) for 5 h before Ca²⁺ imaging (P2; ***p < 0.001 2-sample unpaired t test, n = 23–29 cells, representative of 2 cultures of P2 NPCs).

**Figure 2.**
STIM1 and Orai1 are essential for SOCE in embryonic and neonatal NPCs. A, B, SOCE is significantly diminished in NPCs treated with siSTIM1 and siOrai1 (P2; *p < 0.0001 determined by one-way ANOVA followed by 2-sample unpaired t test, n = 35–82 cells, representative of 3 cultures). C, Western blots showing expression of STIM1 and Orai1 in E13 NPCs and after knock down of these proteins by treatment with siRNA. Nestin was used as the loading control. D, Summary graphs showing relative expression of STIM1 and Orai1 in NPCs after suppression of these molecules (E13 and P2; **p < 0.01, *p < 0.05, unpaired t test, n = 3 blots from 2 cultures). E–G, SOCE is abolished in NPCs derived from homozygous Orai1^R93W/R93W, Orai1^−/−, and STIM1^−/− mice and significantly diminished in heterozygous Orai1^R93W/+, Orai1^+/−, and STIM1^−/− NPCs. H, Summary of the rate of Ca²⁺ entry after re-addition of extracellular Ca²⁺ in the indicated transgenic mice. Ca²⁺ influx rates were estimated by measuring the initial slope of Ca²⁺ entry over 30 s (E18; p < 0.0001, one-way ANOVA followed by *post hoc* 2-sample unpaired t tests between WT and mutant pairs, ***p < 0.001, **p < 0.01, average data from 77–852 cells from 4–13 experiments, from 2–11 mice). I, Summary of the average [Ca²⁺]_i measured 120 s after addition of extracellular Ca²⁺ (E18; p-values determined as in H; [Ca²⁺]_i was averaged over a 30 s duration).

**Figure 3.**
Orai1 is critical for SOCE in adult NPCs. A, Schematic of the targeting strategy for conditional deletion of *Orai1*. The Orai1-targeting construct inserted an FRT2-PGK neocassette flanked by *LoxP* sites around exons 2 and 3 into the WT locus. The genomic organization of that insertion is shown as the recombinant allele. PGKNeo was removed through Flp electroporation of ES cells verified for the insertion by PCR and Southern blot and is shown as the final floxed allele after recombination. Deletion of exons 2 and 3 removes the entire coding region of Orai1. B, PCR of genomic DNA isolated from various tissues in Orai1^+/+:Nes-Cre, Orai1^fl/+:Nes-Cre, and Orai1^{fl/fl:Nes-Cre} mice showing deletion of Orai1 in brain tissue (top). Bottom, Deletion of Orai1 specifically in brain tissue in the Orai1^{fl/fl:Nes-Cre} mouse. OB, Olfactory bulb; CTX, cortex; HC, hippocampus; Panc, pancreas (20-week-old mice representative of 2 PCR experiments from 2 sets of mice). C, SOCE is significantly diminished in adult (24-week-old) Orai1^{fl/fl:Nes-Cre} NPCs. Ca²⁺ influx rates (D) and [Ca²⁺]i (E) are strongly attenuated after re-addition of external Ca²⁺ (12- to 22-week-old mice; ***p < 0.001, unpaired t test, n = 122–237 cells, 3–8 experiments).

**Figure 4.**
NPC maturation regulates SOCE. A, Neurospheres cultured from E13 NPCs express the progenitor marker nestin. Cells were fixed and immunolabeled for nestin ∼16 h after plating. Nuclei were labeled using DAPI. B, Costaining of NPCs with GFAP and Orai1. Cells were imaged at the coverslip interface (images show the cell footprint). NPCs were cultured from P21 mice. C, Orai1 labeling is absent in the Orai1^{fl/−:Nes-Cre} mice, confirming the deletion of Orai1 in these mice (P21) D, Costaining of NPCs for the neuroblast marker DCX and for Orai1. E, Staining of NPCs from Orai1^{fl/−:Nes-Cre} mice for DCX and Orai1. No Orai1 labeling is seen in the Orai1 ^{fl/−:Nes-Cre} mice, as expected from the genetic ablation of Orai1. F, SOCE is diminished in NPCs expressing DCX-GFP compared with GFP⁻ cells. NPCs were isolated from DCX-GFP mice and [Ca²⁺]i was measured using fura-2 as in Figure 1. G, Summary of SOCE amplitude after re-addition of extracellular Ca²⁺ (E15 mice; unpaired t test, ***p < 0.001, n = 13–143 cells, representative of 3 experiments from 2 cultures). H, Images of NPCs expressing DCX-GFP loaded with fura-2. The fura-2 signal is at the 380 nm excitation wavelength. DIC, Dfferential interference contrast.

**Figure 5.**
Stimulation of EGF and muscarinic ACh receptors activates SOCE in NPCs. A, Application of EGF (100 ng/ml) in a Ca²⁺-free Ringer's solution followed by re-addition of extracellular Ca²⁺ elicits a [Ca²⁺]_i elevation that is blocked by La³⁺ (2 μm). The two traces show averages of cells that responded with a rise in [Ca²⁺]i and those that failed to respond after application of EGF. P1 mice, P-values determined by 2-sample unpaired t test, n = 17/29 cells responded to EGF (Resp), while the remainder of the cells did not show increases in [Ca²⁺]i (No Resp). ***p < 0.001, unpaired t test, 17/29 cells responded to EGF (Resp). B, Administration of EGF (100 ng/ml) in the presence of extracellular Ca²⁺ produces a biphasic [Ca²⁺]_i elevation. C, The sustained component of the EGF-stimulated Ca²⁺ signal is eliminated in Orai1-deficient (Orai1^{fl/fl:Nes-Cre}) NPCs (adult 8 weeks old, *p < 0.05, unpaired t test, n = 13–14 cells for each condition, representative of 2 experiments). D, Application of ACh (300 μm) in a Ca²⁺-free Ringer's solution stimulates a transient [Ca²⁺]_i elevation. Re-addition of extracellular Ca²⁺ produces Ca²⁺ entry that is inhibited by atropine (20 nm) and La³⁺ (2 μm). Methyllycaconitine citrate (MLA) and dihydro-β-erythroidine (DHBE) were used in all solutions to block nAChR subunits (8-week-old NPCs, ***p < 0.001 determined by paired t tests, n = 26/33 cells responded to ACh). E, Administration of muscarine (50 μm) in Ca²⁺-free solution triggers ER Ca²⁺ store release. Subsequent re-addition of extracellular Ca²⁺ causes Ca²⁺ influx that is inhibited by La³⁺ (2 μm; adult 8 weeks old, ***p < 0.001, 2-tailed paired t test, n = 10/15 cells responded to muscarine). F, Application of muscarine (50 μm) in the standard extracellular Ringer's solution produces a biphasic [Ca²⁺]_i elevation. The sustained phase of the [Ca²⁺]_i elevation is suppressed in Orai1^R93W/+ NPCs and abolished in Orai1^R93W/R93W NPCs. (P0, one-way ANOVA, p < 0.0001, followed by unpaired t test between WT and each test condition, ***p < 0.001 n = 10–21 cells, representative of 5 experiments from 2 cultures). G, Single-cell Ca²⁺ responses after application of 200 μm muscarine. Ca²⁺ oscillations are seen in ∼50% of the Orai1^R93W/+ NPCs that responded to muscarine (P0, n = 16–18 cells for each condition).

**Figure 6.**
CRAC channels activate NFAT-dependent gene expression in NPCs. A, NPCs were nucleofected with GFP-NFAT1 and imaged 24–48 h later. Images were acquired in 2 mm extracellular Ca²⁺, 15 min after application of 1 μm TG, in a Ca²⁺-free solution, and 15 min after re-addition of 2 mm Ca²⁺. Where indicated, BTP-2 (1 μm) was applied for 3–5 h before the experiment. B, Summary of the percentage of cells showing nuclear translocation of GFP-NFAT1. (E13 and P2; one-way ANOVA, p = 0.0003, followed by unpaired t test between indicated test conditions, *p < 0.05, **p < 0.01, ***p < 0.001, n = 93–133 cells from 3–4 experiments). C, NFAT luciferase activity stimulated by depletion of ER Ca²⁺ stores is significantly suppressed by pretreatment with the CRAC channel inhibitors 2-APB (50 μm), SKF96365 (20 μm), and BTP-2 (0.5 μm) in the presence of low external Ca²⁺ and by cyclosporine A (1 μm; E13; one-way ANOVA, p < 0.0001; unpaired t test between indicated test conditions, **p < 0.01, ***p < 0.001, representative of 3 cultures). D, E, NFAT luciferase activity is diminished by siRNA treatment against STIM1 and Orai1 (P1; one-way ANOVA, p < 0.0001; unpaired t test, **p < 0.01, representative of 3 cultures; D) and in NPCs derived from Orai1^R93W/R93W mice (E18; one-way ANOVA, p < 0.0001; unpaired t test, **p < 0.01; E). F, Muscarine stimulates nuclear translocation of GFP-NFAT1, which is abolished by BTP-2 (1 μm; E13, p < 0.01, unpaired t test, n = 219–461 cells from 4 experiments). G, Theoretical [Ca²⁺]i profiles as a function of distance from an open CRAC channel. The [Ca²⁺] profiles were calculated as described previously (Neher, 1986; Stern, 1992). The single-channel CRAC current was assumed to be 5 fA. H, [Ca²⁺]i elevations produced by SOCE in EGTA- or BAPTA-treated cells. NPCs were loaded with 20 μm EGTA-AM or 20 μm BAPTA-AM for 25–35 min at 37°C. (E13, ***p < 0.001, unpaired t test, n = 58–73 cells; from 2 experiments). I, Nuclear translocation is not significantly affected by intracellular EGTA, but is suppressed by BAPTA (E13 and E14; one-way ANOVA, p = 0.0002; unpaired t test, p = 0.73 for EGTA, and ***p < 0.001 for BAPTA-treated cells, n = 200–233 cells from 3 experiments).

**Figure 7.**
Suppression of STIM1 or Orai1 expression diminishes NPC proliferation. A, NPCs were nucleofected with the indicated siRNA constructs and incorporation of EdU was analyzed by flow cytometry. B, Summary of EdU incorporation for the indicated conditions (E13 and E14 mice; p-values determined by ANOVA followed by *post hoc* paired t tests, *p = 0.05, **p < 0.01, n = 6 experiments). C, Knockdown of Orai1 expression diminishes NPC cell density. Cell density was assessed by an MTT colorimetric assay. The x-axis shows duration in days after nucleofection and seeding of NPCs at day 0 (E13, p = 0.01 at day 5, 2-sample unpaired t test, representative of 3 experiments). D, NPCs derived from adult mice show diminished EdU incorporation after Orai1 knock down. E, Summary of the effects of siRNA knock down of Orai1 (adult mice, 7–10 wk, p = 0.008, 2-sample paired t test, n = 4 experiments from 3 cultures). F, G, The calcineurin inhibitor cyclosporin A (5 μm) diminishes NPC proliferation. NPCs were treated with CsA once every 24 h for 48 h before EdU incorporation (E13 and E14, *p < 0.05, paired t test, n = 3 experiments).

**Figure 8.**
Proliferation is diminished in NPCs from transgenic mice lacking functional Orai1 channels. A, EdU analysis of embryonic NPCs from Orai1^+/+ and Orai1^R93W/R93W mice grown in FGF (10 ng/ml) or FGF and EGF (10 ng/ml each). NPCs were grown for 24–48 h before EdU labeling (3–8 h). B, Summary of the fraction of EdU-labeled cells under different growth conditions. EGF-stimulated proliferation of NPCs is attenuated in Orai1^R93W/R93W NPCs (E13–E14, 2-way ANOVA followed by *post hoc t* test, n = 8–19 experiments/mice for each genotype, 5 cultures; *p < 0.05, **p < 0.01, ***p < 0.001). C, MTT cell growth assays show decreased NPC cell densities in Orai1^R93W/R93W mice. Right, Same experiment on a magnified y-axis scale to better visualize the difference between Orai1^R93W/R93W and WT cells grown in FGF alone (E13, *p < 0.05, **p < 0.01 unpaired t test, n = 3 experiments, representative of 3 cultures). D, Apoptosis is not significantly different in NPCs lacking functional CRAC channels. Representative flow cytometry analysis depicting the fraction of live (Q3), apoptotic (Q4), and dead cells (Q2) in WT and Orai1^R93W/R93W NPCs. The percentage of apoptotic cells is indicated in the bottom right box. E14 embryos were used for this experiment.

**Figure 9.**
Adult mice lacking Orai1 exhibit diminished NSC proliferation *in vivo* and *in vitro*. A, B, Whole-mount images of coronal brain sections containing the SVZ from Orai1^fl/fl (A) or Orai1^{fl/fl:Nes-Cre} mice (B; low-magnification images are on shown on the left). Example confocal images at a high magnification (60×) of BrdU immunostaining (red) and DAPI (cyan) in the dorsolateral SVZ are shown on the right. Images were collected in the dorsolateral SVZ. C, Summary of the average number of BrdU-labeled cells per section in WT and KO mice (adult mice, 6 weeks old, ***p < 0.001, unpaired t test; 12–13 sections analyzed from 3 mice for each condition). D, TUNEL staining does not show significant levels of ongoing apoptosis or necrosis in Orai1^fl/fl or Orai1^{fl/fl:Nes-Cre} mice. E, F, MTT colorimetric cell growth assays in NPCs obtained from adult Orai1^R93W/+ NPCs (9 weeks old) or Orai1^{fl/fl:Nes-Cre} mice (11 weeks old; *p < 0.05, **p < 0.01, unpaired t test, n = 3 experiments). Cells were seeded at day 0.

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References

1. Adler EM, Augustine GJ, Duffy SN, Charlton MP. Alien intracellular calcium chelators attenuate neurotransmitter release at the squid giant synapse. J Neurosci. 1991;11:1496–1507. - PMC - PubMed
1. Altman J. Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb. J Comp Neurol. 1969;137:433–457. doi: 10.1002/cne.901370404. - DOI - PubMed
1. Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol. 1965;124:319–335. doi: 10.1002/cne.901240303. - DOI - PubMed
1. Baba A, Yasui T, Fujisawa S, Yamada RX, Yamada MK, Nishiyama N, Matsuki N, Ikegaya Y. Activity-evoked capacitative Ca2+ entry: implications in synaptic plasticity. J Neurosci. 2003;23:7737–7741. - PMC - PubMed
1. Bates B, Rios M, Trumpp A, Chen C, Fan G, Bishop JM, Jaenisch R. Neurotrophin-3 is required for proper cerebellar development. Nat Neurosci. 1999;2:115–117. doi: 10.1038/5669. - DOI - PubMed

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[1] Adler EM, Augustine GJ, Duffy SN, Charlton MP. Alien intracellular calcium chelators attenuate neurotransmitter release at the squid giant synapse. J Neurosci. 1991;11:1496–1507. - PMC - PubMed

[2] Adler EM, Augustine GJ, Duffy SN, Charlton MP. Alien intracellular calcium chelators attenuate neurotransmitter release at the squid giant synapse. J Neurosci. 1991;11:1496–1507. - PMC - PubMed

[3] Altman J. Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb. J Comp Neurol. 1969;137:433–457. doi: 10.1002/cne.901370404. - DOI - PubMed

[4] Altman J. Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb. J Comp Neurol. 1969;137:433–457. doi: 10.1002/cne.901370404. - DOI - PubMed

[5] Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol. 1965;124:319–335. doi: 10.1002/cne.901240303. - DOI - PubMed

[6] Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol. 1965;124:319–335. doi: 10.1002/cne.901240303. - DOI - PubMed

[7] Baba A, Yasui T, Fujisawa S, Yamada RX, Yamada MK, Nishiyama N, Matsuki N, Ikegaya Y. Activity-evoked capacitative Ca2+ entry: implications in synaptic plasticity. J Neurosci. 2003;23:7737–7741. - PMC - PubMed

[8] Baba A, Yasui T, Fujisawa S, Yamada RX, Yamada MK, Nishiyama N, Matsuki N, Ikegaya Y. Activity-evoked capacitative Ca2+ entry: implications in synaptic plasticity. J Neurosci. 2003;23:7737–7741. - PMC - PubMed

[9] Bates B, Rios M, Trumpp A, Chen C, Fan G, Bishop JM, Jaenisch R. Neurotrophin-3 is required for proper cerebellar development. Nat Neurosci. 1999;2:115–117. doi: 10.1038/5669. - DOI - PubMed

[10] Bates B, Rios M, Trumpp A, Chen C, Fan G, Bishop JM, Jaenisch R. Neurotrophin-3 is required for proper cerebellar development. Nat Neurosci. 1999;2:115–117. doi: 10.1038/5669. - DOI - PubMed

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Store-operated CRAC channels regulate gene expression and proliferation in neural progenitor cells

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Store-operated CRAC channels regulate gene expression and proliferation in neural progenitor cells

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