A critical role for STIM1 in filopodial calcium entry and axon guidance
© Shim et al.; licensee BioMed Central Ltd. 2013
Received: 5 November 2013
Accepted: 23 November 2013
Published: 1 December 2013
Stromal interaction molecule 1 (STIM1), a Ca2+ sensor in the endoplasmic reticulum, regulates store-operated Ca2+ entry (SOCE) that is essential for Ca2+ homeostasis in many types of cells. However, if and how STIM1 and SOCE function in nerve growth cones during axon guidance remains to be elucidated.
We report that STIM1 and transient receptor potential channel 1 (TRPC1)-dependent SOCE operates in Xenopus spinal growth cones to regulate Ca2+ signaling and guidance responses. We found that STIM1 works together with TRPC1 to mediate SOCE within growth cones and filopodia. In particular, STIM1/TRPC1-dependent SOCE was found to mediate oscillatory filopodial Ca2+ transients in the growth cone. Disruption of STIM1 function abolished filopodial Ca2+ transients and impaired Ca2+-dependent attractive responses of Xenopus growth cones to netrin-1. Finally, interference with STIM1 function was found to disrupt midline axon guidance of commissural interneurons in the developing Xenopus spinal cord in vivo.
Our data demonstrate that STIM1/TRPC1-dependent SOCE plays an essential role in generating spatiotemporal Ca2+ signals that mediate guidance responses of nerve growth cones.
KeywordsAxon guidance STIM1 SOCE TRPC1 Calcium Netrin-1 Filopodial Ca2+ entry Ca2+ oscillation Calcium homeostasis
Guided axonal growth and regeneration depend on the motile growth cone at the tip of axons to extend and navigate through a complex environment to reach specific targets for neuronal connections. It is well established that the nerve growth cone needs to maintain an optimal range of intracellular Ca2+ concentration ([Ca2+]i) for its motility and responses to extracellular cues . The cytoplasmic Ca2+ homeostasis is regulated by Ca2+ entry from the extracellular environment, internal Ca2+ release and replenishment of the intracellular store [2, 3]. However, how neuronal growth cones coordinate guidance cue-induced Ca2+ influx, internal Ca2+ release and Ca2+ store replenishment to maintain proper guidance behaviors is unknown. Store-operated Ca2+ entry (SOCE) was originally characterized in non-excitable cells as an indispensable Ca2+ influx mechanism to replenish internal stores [2, 3]. It is triggered by Ca2+ depletion from ER through the ER Ca2+ sensor protein, stromal interacting molecule 1 (STIM1). In response to Ca2+ depletion, STIM1 oligomerizes and translocates to ER and plasma membrane junctions, where it interacts with and activates store-operated Ca2+ (SOC) channels that include TRPC1 and Orai1 proteins [2, 3].
In the nervous system, SOCE has been seen to exist in a number of cell types [4–7] and implicated in synaptic plasticity, axon branching, neuropathic pain and fly motor circuit function [6–10]. However, the existence of SOCE and STIM1, and their potential contribution to the intracellular Ca2+ homeostasis and signaling in axon guidance is not well established. Axonal growth cones are highlighted by two types of actin-based motile membrane protrusions, filopodia and lamellipodia . Of these two structures, lamellipodia are considered to be responsible for growth cone locomotion, whereas filopodia are believed to function in sensing of the environment during axon pathfinding [11–13]. Interestingly, rapid Ca2+ transients in growth cone filopodia have been shown to be involved in growth cone responses to extracellular cues [14, 15]. But how Ca2+ signals are generated in filopodia and whether SOCE is involved in this process remain unknown. Here we report that SOCE operates in Xenopus spinal growth cones and depends on STIM1 and TRPC1. Importantly, we find that SOCE mediates spontaneous and netrin-1-potentiated filopodial Ca2+ entries within growth cones. We further provide evidence that STIM1- and TRPC1-dependent SOCE is required for attractive guidance responses of growth cones to netrin-1. Finally, we show that STIM1 is required for midline axon guidance of commissural interneurons in the developing Xenopus spinal cord in vivo. Our data suggest that SOCE is an essential component of intracellular Ca2+ homeostasis and signaling that regulate neuronal growth cone guidance.
Cloning and expression of Xenopus STIM1
STIM1- and TRPC1-dependent SOCE in Xenopus neuronal growth cones
STIM1-dependent SOCE mediates netrin-1-induced Ca2+ elevation in growth cones
Netrin-1 is known to guide axonal growth cone through a Ca2+-dependent pathway [1, 18] and netrin-1-induced increase in [Ca2+]i in growth cones requires both intracellular Ca2+ release and Ca2+ influx through channels on the plasma membrane [19–21]. Consistent with previous studies [21–23], bath application of netrin-1 (10 ng/ml final concentration) induced a significant rise in [Ca2+]i in Xenopus growth cones (Figure 2E). Importantly, overexpression of XSTIM1-DN abolished the sustained Ca2+ elevation within neuronal growth cones in response to netrin-1 (Figure 2E). Previous studies from ours and others have shown that TRPC1 is required for netrin-1-induced sustained Ca2+ elevation [21, 23]. We have observed an association of TRPC1 with STIM1 in Xenopus brain lysates (Additional file 2: Figure S2), similar to what has been shown in mammalian cells [2, 16, 24]. Therefore, netrin-1 may activate STIM1-dependent SOCE through TRPC1 in neuronal growth cones.
STIM1-dependent SOCE generates filopodial Ca2+ entries in Xenopus neuronal growth cones
Bath application of netrin-1 (10 ng/ml final concentration) was found to potentiate both the incidence and frequency of filopodial Ca2+ entries of Xenopus spinal growth cones (Figure 4D-F; Additional file 9: Movie 7), consistent with previous study using Fluo-4 . We found that this increase in filopodial Ca2+ entries by netrin-1 was abolished when STIM1 function was inhibited by XSTIM1-DN (Figure 4E and F). Over-expression of morpholino against XTRPC1 (XTRPC1-MO) also compromised the potentiation of filopodial Ca2+ entries by netrin-1 (Figure 4E and F). Therefore, STIM1/TRPC1-dependent SOCE mediates the netrin-1-dependent potentiation of oscillatory filopodial Ca2+ entries in neuronal growth cones.
The membrane tethered calcium indicator lck-GCaMP3 also provides an opportunity to map the entry sites of Ca2+ in filopodia. We thus analyzed the sites of initial filopodial Ca2+ entry in Xenopus growth cones by kymography analysis. We found that, although the initial sites of Ca2+ entry distributed throughout the length of a filopodium, a large portion of the Ca2+ entry sites (42-59%) were found at the filopodial tip (Figure 4G). When filopodial Ca2+ entries under different conditions (store-operated, spontaneous, and netrin-1-induced) were examined, no difference was seen on the location of Ca2+ entry sites in filopodia (Figure 4G). Therefore, the tip of the filopodia appears to be the primary site of SOCE-mediated Ca2+ entry in nerve growth cones.
XSTIM1 is required for growth cone guidance
Ca2+ is a key second messenger that mediates a wide range of neuronal activity and responses to extracellular stimuli . Spatiotemporally-restricted Ca2+ signals can steer growth cones in responses to extracellular guidance cues and are thought to be generated from Ca2+ influx through the plasma membrane as well as Ca2+ release from internal store [1, 18]. However, how these two events are coupled to sustain Ca2+ signaling during guidance responses remain unclear. SOCE is believed to be a part of the intracellular Ca2+ homeostasis machinery that maintains [Ca2+]i for various neuronal functions, including optimal growth cone motility. The function of SOCE is well established in non-excitable cells and considered as a Ca2+ entry mechanism for refilling intracellular Ca2+ stores. The molecular components of SOCE include STIM, Orai, and TRP channels, which have also been identified and characterized mostly in non-excitable cells [2, 3]. More recently, several studies support the presence and functional implication of SOCE in the nervous system [4–9], but the molecular composition and functional role of SOCE and STIM1 in neuronal growth cone guidance is not well established. Our data demonstrate that STIM1- and TRPC1-dependent SOCE not only operates in neuronal growth cones but also mediates filopodial Ca2+ transients and growth cone guidance both in vitro and vivo [20, 30, 31]. Our results are consistent with a recent report showing that STIM1 and Orai, two components of SOCE, are involved in growth cone responses to brain derived neurotrophic factor and Semaphorin-3a . Importantly, our study has further identified that TRPC1 is also an essential component of SOCE and a major site of SOCE-mediated Ca2+ entry is in the filopodia, especially at the tip of the filopodia. Moreover, we have presented in vivo evidence that STIM1 is required for proper guidance of commissural axons in developing spinal cord, a classic example of netrin-1-dependent long-range growth cone guidance [20, 30, 31]. Together, the current study has clearly established a role for SOCE, involving STIM1 and TRPC1, in mediating filopodial Ca2+ entries underlying axonal growth cone guidance.
At this moment, the precise mechanism by which STIM1 and SOCE are involved in netrin-1-induced Ca2+ signaling for growth cone attraction remains unclear. Netrin-1 is known to elicit Ca2+ signals by Ca2+ influx through TRPC1 and Ca2+ release from the internal stores to induce growth cone attraction [1, 18–20] but the underlying mechanism remains unclear. It has been shown that brain derived neurotrophic factor (BDNF) triggers Ca2+ release from internal stores through activation of the PLC-γ and IP3 pathway, which in turn induces SOCE through STIM1-TRPC activation [18, 32–34]. Netrin-1 is considered to be in the same group of Ca2+-mediated guidance cues with BDNF. Given that PLC-γ and IP3-induced Ca2+ release are involved in growth cone extension and navigation [22, 34–36], we propose that netrin-1 may initiate intracellular Ca2+ release through activation of netrin-1 receptor Deleted in Colorectal Cancer (DCC), PLC-γ and IP3 production, which further triggers store-depletion, STIM1 activation, and Ca2+ influx through TRPC1 for replenishing ER Ca2+. This notion is further supported by the findings that both netrin-1 and BDNF activate PLC-γ and Phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis in neurite elongation [37, 38]. Therefore, our results provide additional evidence for the conserved signaling pathways among Ca2+-mediated guidance cues and between netrin-1 and neurotrophins.
The role of TRPC channels as SOC has been controversial, but multiple lines of evidences support TRPC as a strong candidate component of store-operated Ca2+ channels. For example, TRPC1 has been shown to be bound and activated by STIM1 and contribute to SOCE in some cells [16, 17, 39–41]. We found that STIM1 interacts with TRPC1 in embryonic neural tissues (Additional file 2: Figure S2) and that TRPC1 knockdown inhibits STIM1-mediated SOCE within growth cones and filopodia (Figures 2D, 3D and 3E), suggesting that TRPC1 is an essential component of SOCE. As STIM1 is also required for netrin-1-induced Ca2+ elevation and growth cone attraction which was shown to be mediated by TRPC1, our data support a role for STIM1 in activating TRPC1. However, we cannot rule out the possibility that STIM1 may affect Ca2+ signaling and growth cone guidance by other mechanisms, such as its effects on cAMP signaling or ER remodeling [42, 43]. Recent studies also showed biochemical assembly of STIM1-TRPCs-Orai complex and functional connections between TRPC channels and Orai1 [41, 44, 45]. STIM1-Orai1 co-localization in response to Ca2+ depletion was reported in neuronal growth cones . Therefore, it is possible that Orai also plays a role in netrin-1 signaling and guidance.
It should be noted that Lck-GCaMP3 was successfully used in distinguishing the Ca2+ signals from membrane entry from internal release from the stores [25, 46]. Our data with Lck-GCaMP3 showing the presence of filopodial Ca2+ transients and its potentiation by netrin-1 is consistent with the previous reports using Fluo-4 [14, 15, 26]. However, when compared with previous studies using Fluo-4, the incidence and frequency of filopodial Ca2+ transients observed in our study appear to be lower than those seen in the previous reports. The difference may be attributed to two possibilities. First, Lck-GCaMP3 detects Ca2+ entry events only at near-plasma membrane regions. However, fluo-4 could detect cytosol Ca2+ changes from other sources such as intracellular stores, which will likely be missed by Lck-GCaMP3. In this regard, Lck-GCaMP3 fluorescence Ca2+ signals may be better called “filopodial Ca2+ entries” rather than filopodial Ca2+ transients. Second, we did not count the Ca2+ transients propagated from the growth cone proper and only counted the Ca2+ entry events generated within the filopodium independently of Ca2+ transients from the growth cone proper. Therefore, our data do not contradict the previous work.
It is of interest to see that the initial site of filopodial Ca2+ entry is largely localized to the tip of filopodia. Filopodia are considered to be the sensory apparatus for growth cones as they extend farther distance to detect the environmental signals. Therefore, it makes sense to have the sensory molecules accumulated at the tip for signal transduction initiation. However, the lack of quality antibodies prevented us from convincingly detecting the localization of STIM1/TRPC1 and other SOCE components at the filopodial tip. On the other hand, it has been reported that several receptors such as integrins, TRPC1 and DCC [14, 26, 47] and signaling molecules such as Src, PAK, PKA [48, 49] are enriched at the tip of filopodia along with many other cytoskeleton regulatory molecules [11, 50, 51]. Therefore, it is conceivable that STIM1 and TRPC1 could function at the filopodial tip as an effective way to sense the environment and initiate Ca2+ signaling during growth cone guidance.
We report fast, highly localized and periodic spontaneous filopodial Ca2+ entries initiated independently of growth cone Ca2+ transients, which was consistent with the previous reports of oscillatory pattern of spontaneous Ca2+ transients within growth cone and filopodia during axonal growth [14, 15, 52]. The critical role for TRPC1 in generation of filopodial Ca2+ entry and its potentiation by netrin-1 is also consistent with the previous reports [14, 15, 26]. A further unexpected result was that STIM1-DN mutant blocked not only the SOCE-induced filopodial Ca2+ entries that depend on STIM1 but also spontaneous and netrin-1-potentiated oscillatory filopodial Ca2+ entries, suggesting that STIM1-dependent SOCE mediates the generation and maintenance of filopodial Ca2+ entries. Thus, our visualization of oscillatory patterns of spontaneous filopodial Ca2+ entries and their inhibition by STIM1- or TRPC1-knockdown is the first demonstration of a role of STIM/TRPC1-dependent SOCE in regulating Ca2+ oscillation in neurons, which is consistent with previous findings in other cell types [53–55]. It is plausible that store Ca2+ release, transient drop in ER Ca2+, and Ca2+ entry through TRPC1 triggered by transient STIM1 activation may underlie the Ca2+ oscillations seen in growth cone filopodia. Thus, considering the functional correlation between the frequency of filopodial Ca2+ transients and growth cone outgrowth and turning [14, 26], disruption of STIM1 or TRPC1 function is likely to result in the breakup of Ca2+ cycling for oscillations and subsequent attenuated frequency of filopodial Ca2+ entries, which may further cause the suppression of growth cone guidance in response to netrin-1.
Our data demonstrate a role for STIM1/TRPC1-dependent SOCE in mediating oscillatory patterns of spontaneous and netrin-1-potentiated filopodial Ca2+ entries that underlie axonal growth cone guidance both in vitro and in vivo.
Xenopus STIM1 (XSTIM1) [GenBank: BC126011] was identified by BLAST searches of the GenBank database using human STIM1 cDNA sequence. The coding region of XSTIM1 gene was isolated by RT-PCR, sequenced and cloned into the pCS2 vector (gift of D. Turner, University of Michigan). The following constructs of XSTIM1 and its mutants were generated by site-directed mutagenesis (Strategene) or by PCR based on previous studies of mammalian STIM1 mutants : YFP-XSTIM1-WT, YFP-XSTIM1-DN, YFP-XSTIM1-CA, and mCherry-XSTIM1-DN (Figure 2A). Different XSTIM constructs were in vitro transcribed with the mMESSAGE mMACHINE SP6 kit (Ambion). pN1-Lck-GCaMP3 plasmid was obtained from Addgene (plasmid #26974, ), cloned into pCS2 vector using BamHI and XbaI sites and in vitro transcribed with mMESSAGE mMACHINE SP6 kit (Ambion).
Xenopus embryo injection and spinal neuron culture
Blastomere injections of mRNAs or morpholinos into early stages of Xenopus embryos and culturing of spinal neurons from these injected embryos were performed as previously described [20, 23, 29, 56]. Briefly, fertilized embryos were injected at the two- or four-cell stage with mRNA (2-3 ng/embryo). A control morpholinos or morpholinos specific for Xenopus TRPC1 (XTRPC1-MO) was previously described . Uninjected or injected embryos at stage 22 were used for cultures of spinal neurons as previous described [20, 23]. All the procedures involving Xenopus frogs and embryos were carried out in accordance to the NIH guideline for animal use and have been approved by the Institutional Animal Care and Use Committee (IACUC) of Emory University.
RT-PCR and Whole-mount in situ hybridization of Xenopus embryos
Neural tube and notochord were isolated from the dorsal section of the stage 25-26 Xenopus embryos after dissection with microsurgical scissors and incubation with collagenase (type I, Sigma). Total RNA was prepared by using TRIzol Reagent (invitrogen) and treated with the RNase-free DNAse I (Roche) to remove genomic DNA. The extracted RNA was reverse transcribed by using M-MLV reverse transcriptase (Invitrogen) and random hexamers (Roche). PCR amplification was performed using Taq polymerase (Fermentas). The –RT lane is the negative control of the RT-PCR on neural tube tissue RNA in the absence of a reverese transcriptase. The PCR primers are as follows; XSTIM1-forward, 5′ CCAGAACCTTGGAAGAGGTG 3′, XSTIM1-reverse, 5′ GACTGAATGGTACCGGCTGT 3′; XODC-forward, 5′ CAGCTAGCTGTGGTGTGG 3′, XODC-rev, 5′ CAACATGGAAACTCACACC 3′. For whole-mount in situ hybridization, the digoxigenin (DIG)-UTP-labelled antisense RNA was used as previously described [23, 57]. The C-terminal region of XSTIM1 corresponding to amino acid 192-668 was used for the specific anti-sense and sense probes. The labelled probe was detected with alkaline phosphatase-conjugated anti-DIG antibody (Fab fragments) and visualized with the BM purple AP substrate (Roche Applied Science). Selected embryos from whole-mount in situ hybridization were embedded in a sucrose and Tissue-Tek O.C.T medium, completely frozen and cross-sectioned at 40 μm with a cryostat (Leica CM1850).
Xenopus spinal neuron cultures were fixed in 4% paraformaldehyde in a cacodylate buffer (0.1 M sodium cacodylate, 0.1 M sucrose, pH 7.4) for 30 minutes and permeabilized with Triton X-100 (0.1%) for 10 minutes. The cells were incubated with a rabbit polyclonal antibody against full length human STIM1 (MyBioScource) at a dilution of 1:50 after blocking with 5% goat serum and labelled with Alexa Fluor 546 goat anti-rabbit secondary (Invitrogen). Fluorescent imaging was captured on an inverted microscope (Nikon Eclipse Ti-E).
Growth cone turning assay
Microscopic gradients of netrin-1 (5 μg/ml in the pipette) were produced as previously described [29, 56, 58, 59]. Xenopus spinal neurons derived from injected blastomeres were identified under fluorescent microscope and used for turning assay at the room temperature 14 to 20 hrs after plating as previously described [20, 23, 29, 56]. The culture was plated on glass coverslip without any coating. The turning angle was defined by the angle between the original direction of neurite extension and a straight line connecting the positions of the center of the growth cone at the onset and the end of the 30 min period. The rates of neurite extension were calculated based on the net neurite extension during the turning assay. Only those growth cones of isolated neurons with a net neurite extension > 5 μm over the 30-min period were included for analysis. Statistical significance was assessed using the Bootstrap-test.
Ca2+ imaging of cultured Xenopus spinal neurons
Ca2+ imaging of cultured growth cones of Xenopus spinal neurons was performed as previously described [23, 29, 56]. Specifically, isolated Xenopus spinal neurons were cultured on glass coverslip without coating, loaded with Fluo-4 AM (2 μM, Molecular Probes) for 30 minutes, rinsed with the Modified Ringer used for growth cone turning assay, and imaged after bath-application of netrin-1 (10 ng/ml). For store-operated Ca2+ entry experiment, neurons were bathed in Ca2+ -free media with CPA (25 μM) to deplete intracellular Ca2+ stores, and imaged after re-addition of extracellular Ca2+ (1.5 mM). Growth cones expressing mCherry-XSTIM1-DN proteins were identified under fluorescent microscope and selected for further Ca2+ imaging. Imaging was carried out using a Zeiss 510 META system equipped with a 20X objective (NA 0.8). Excitation was at 488 nm by argon laser and the emitted fluorescence was collected at 500-560 nm. Fluorescence and bright-field images were simultaneously acquired at every 30 seconds with a frame scan. The mean fluorescence intensity of each time point was measured over a fixed circular region of interest that covers the entire growth cone and normalized to the average fluorescence intensity that was measured during a 2 minutes baseline period (prior to the netrin-1 application or addition of 1.5 mM Ca2+ solution).
For filopodial Ca2+ imaging, Lck-GCaMP3 mRNA was injected into early staged embryos without or with other mRNAs or morpholino. Spinal neurons were cultured on the glass coverslip coated with poly-D-lysine and laminin, which increases the number and length of filopodia , in serum-free culture medium. In our netrin-1-induced filopodial Ca2+ entries experiments, the spinal neurons were incubated in MR solution with the addition of cAMP analog Sp-cAMP (25 μM) to counterbalance the laminin’s effect of reducing cAMP levels in growth cones  and mimic the condition of our in vitro turning assay where laminin coating on the glass culture dish was omitted. Live cell imaging of Ca2+ transients was performed on an inverted microscope (Nikon Eclipse Ti-E) equipped with a 60X Apo TIRF objective (NA 1.49), and EMCCD camera (Photometrics) using NIS-Elements software (Nikon). Excitation was at 488 nm and the emitted fluorescence was collected at 520 nm and Lck-GCaMP3 fluorescence images were acquired at every 200 milliseconds. To determine several characteristics of filopodial Ca2+ entries, including the incidence, frequency and initiation sites of transients, the Kymographs (spatio-temporal map) were created from the images of the user-defined segmented line one pixel in width spanning the filopodium from the time-lapse movies with NIH ImageJ software. Grayscale values for this linear region of interest (ROI) for each frame of the time series were transformed into pseudocolored images to show time-dependent changes in intracellular Ca2+ concentration ([Ca2+]i) along the length of the ROI (y-axis) over time (x-axis).
Immunoprecipitation and immunoblotting
For co-immunoprecipitation, protein lysates were prepared from the Xenopus brain explants including spinal cords dissected from the embryos at stage 26-28 using lysis buffer containing 1% Triton X-100, 150 mM NaCl, 10 mM Tris-Cl (pH 7.4), 1 mM EDTA, 1 mM EGTA, 0.5% Nonidet P-40, 0.2 mM Na-orthovanadate, and protease inhibitor cocktail. They were incubated with the appropriate antibody for 3-4 hours at 4°C, followed by incubation with protein A/G agarose beads (Pierce) for overnight at 4°C. Mouse anti-c-Myc monoclonal antibody (Roche Applied Science) and rabbit anti-GFP polyclonal antibody (Abcam) were used for immunoprecipitation and immunoblotting.
Embryos at stage 25-26 were fixed and processed for immunocytochemistry as previously described [20, 23, 62]. Monoclonal antibody 3A10, specific for commissural interneurons [23, 63], was obtained from the Developmental Studies Hybridoma Bank at the University of Iowa and used at a dilution of 1:100. Secondary antibodies were used at a dilution of 1:250. Confocal images of sagittal views of embryos were taken with a Zeiss LSM 510 META system and Z-series reconstructions were processed with the Zeiss LSM image acquisition program as previously described . Statistical significance was assessed using the Bootstrap-test.
We thank P.F. Worley for help and discussion. This work was supported in part by grants from National Institutes of Health to JQZ (GM083889 and GM084363) and to GLM. (NS048271 and HD069184).
- Zheng JQ, Poo MM: Calcium signaling in neuronal motility. Annu Rev Cell Dev Biol. 2007, 23: 375-404. 10.1146/annurev.cellbio.23.090506.123221.View ArticlePubMedGoogle Scholar
- Cahalan MD: STIMulating store-operated Ca(2+) entry. Nat Cell Biol. 2009, 11: 669-677. 10.1038/ncb0609-669.PubMed CentralView ArticlePubMedGoogle Scholar
- Lewis RS: Store-operated calcium channels: new perspectives on mechanism and function. Cold Spring Harb Perspect Biol. 2011, 3 (12): doi: 10.1101/cshperspect.a003970Google Scholar
- Kachoei BA, Knox RJ, Uthuza D, Levy S, Kaczmarek LK, Magoski NS: A store-operated Ca(2+) influx pathway in the bag cell neurons of Aplysia. J Neurophysiol. 2006, 96: 2688-2698. 10.1152/jn.00118.2006.PubMed CentralView ArticlePubMedGoogle Scholar
- Li D, Herault K, Oheim M, Ropert N: FM dyes enter via a store-operated calcium channel and modify calcium signaling of cultured astrocytes. Proc Natl Acad Sci U S A. 2009, 106: 21960-21965. 10.1073/pnas.0909109106.PubMed CentralView ArticlePubMedGoogle Scholar
- Gemes G, Bangaru ML, Wu HE, Tang Q, Weihrauch D, Koopmeiners AS, Cruikshank JM, Kwok WM, Hogan QH:Store-operated Ca2+entry in sensory neurons: functional role and the effect of painful nerve injury.J Neurosci. 2011, 31: 3536-3549. 10.1523/JNEUROSCI.5053-10.2011.PubMed CentralView ArticlePubMedGoogle Scholar
- Venkiteswaran G, Hasan G:Intracellular Ca2+signaling and store-operated Ca2+entry are required in Drosophila neurons for flight.Proc Natl Acad Sci U S A. 2009, 106: 10326-10331. 10.1073/pnas.0902982106.PubMed CentralView ArticlePubMedGoogle Scholar
- Tang F, Kalil K: Netrin-1 induces axon branching in developing cortical neurons by frequency-dependent calcium signaling pathways. J Neurosci. 2005, 25: 6702-6715. 10.1523/JNEUROSCI.0871-05.2005.View ArticlePubMedGoogle Scholar
- 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.PubMedGoogle Scholar
- Steinbeck JA, Henke N, Opatz J, Gruszczynska-Biegala J, Schneider L, Theiss S, Hamacher N, Steinfarz B, Golz S, Brustle O, et al: Store-operated calcium entry modulates neuronal network activity in a model of chronic epilepsy. Exp Neurol. 2011, 232: 185-194. 10.1016/j.expneurol.2011.08.022.View ArticlePubMedGoogle Scholar
- Geraldo S, Gordon-Weeks PR: Cytoskeletal dynamics in growth-cone steering. J Cell Sci. 2009, 122: 3595-3604. 10.1242/jcs.042309.PubMed CentralView ArticlePubMedGoogle Scholar
- Zheng JQ, Wan JJ, Poo MM: Essential role of filopodia in chemotropic turning of nerve growth cone induced by a glutamate gradient. J Neurosci. 1996, 16: 1140-1149.PubMedGoogle Scholar
- Davenport RW, Dou P, Rehder V, Kater SB: A sensory role for neuronal growth cone filopodia. Nature. 1993, 361: 721-724. 10.1038/361721a0.View ArticlePubMedGoogle Scholar
- Gomez TM, Robles E, Poo M, Spitzer NC: Filopodial calcium transients promote substrate-dependent growth cone turning. Science. 2001, 291: 1983-1987. 10.1126/science.1056490.View ArticlePubMedGoogle Scholar
- Nicol X, Hong KP, Spitzer NC: Spatial and temporal second messenger codes for growth cone turning. Proc Natl Acad Sci U S A. 2011, 108: 13776-13781. 10.1073/pnas.1100247108.PubMed CentralView ArticlePubMedGoogle Scholar
- Huang GN, Zeng W, Kim JY, Yuan JP, Han L, Muallem S, Worley PF: STIM1 carboxyl-terminus activates native SOC, I(crac) and TRPC1 channels. Nat Cell Biol. 2006, 8: 1003-1010. 10.1038/ncb1454.View ArticlePubMedGoogle Scholar
- Liu X, Cheng KT, Bandyopadhyay BC, Pani B, Dietrich A, Paria BC, Swaim WD, Beech D, Yildrim E, Singh BB, et al:Attenuation of store-operated Ca2+current impairs salivary gland fluid secretion in TRPC1(-/-) mice.Proc Natl Acad Sci U S A. 2007, 104: 17542-17547. 10.1073/pnas.0701254104.PubMed CentralView ArticlePubMedGoogle Scholar
- Tojima T, Hines JH, Henley JR, Kamiguchi H: Second messengers and membrane trafficking direct and organize growth cone steering. Nature reviews Neuroscience. 2011, 12: 191-203. 10.1038/nrn2996.PubMed CentralView ArticlePubMedGoogle Scholar
- Hong K, Nishiyama M, Henley J, Tessier-Lavigne M, Poo M: Calcium signalling in the guidance of nerve growth by netrin-1. Nature. 2000, 403: 93-98. 10.1038/47507.View ArticlePubMedGoogle Scholar
- Shim S, Goh EL, Ge S, Sailor K, Yuan JP, Roderick HL, Bootman MD, Worley PF, Song H, Ming GL: XTRPC1-dependent chemotropic guidance of neuronal growth cones. Nat Neurosci. 2005, 8: 730-735. 10.1038/nn1459.PubMed CentralView ArticlePubMedGoogle Scholar
- Wang GX, Poo MM: Requirement of TRPC channels in netrin-1-induced chemotropic turning of nerve growth cones. Nature. 2005, 434: 898-904. 10.1038/nature03478.View ArticlePubMedGoogle Scholar
- Tojima T: Intracellular signaling and membrane trafficking control bidirectional growth cone guidance. Neurosci Res. 2012, 73: 269-274. 10.1016/j.neures.2012.05.010.View ArticlePubMedGoogle Scholar
- Shim S, Yuan JP, Kim JY, Zeng W, Huang G, Milshteyn A, Kern D, Muallem S, Ming GL, Worley PF: Peptidyl-prolyl isomerase FKBP52 controls chemotropic guidance of neuronal growth cones via regulation of TRPC1 channel opening. Neuron. 2009, 64: 471-483. 10.1016/j.neuron.2009.09.025.PubMed CentralView ArticlePubMedGoogle Scholar
- Hogan PG, Lewis RS, Rao A: Molecular basis of calcium signaling in lymphocytes: STIM and ORAI. Annu Rev Immunol. 2010, 28: 491-533. 10.1146/annurev.immunol.021908.132550.PubMed CentralView ArticlePubMedGoogle Scholar
- Shigetomi E, Kracun S, Khakh BS: Monitoring astrocyte calcium microdomains with improved membrane targeted GCaMP reporters. Neuron Glia Biol. 2010, 6: 183-191. 10.1017/S1740925X10000219.PubMed CentralView ArticlePubMedGoogle Scholar
- Kerstein PC, Jacques-Fricke BT, Rengifo J, Mogen BJ, Williams JC, Gottlieb PA, Sachs F, Gomez TM: Mechanosensitive TRPC1 channels promote calpain proteolysis of talin to regulate spinal axon outgrowth. J Neurosci. 2013, 33: 273-285. 10.1523/JNEUROSCI.2142-12.2013.PubMed CentralView ArticlePubMedGoogle Scholar
- Soboloff J, Rothberg BS, Madesh M, Gill DL: STIM proteins: dynamic calcium signal transducers. Nature reviews Molecular cell biology. 2012, 13: 549-565. 10.1038/nrm3414.PubMed CentralView ArticlePubMedGoogle Scholar
- Song H, Ming G, He Z, Lehmann M, McKerracher L, Tessier-Lavigne M, Poo M: Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides. Science. 1998, 281: 1515-1518.View ArticlePubMedGoogle Scholar
- Ming GL, Song HJ, Berninger B, Holt CE, Tessier-Lavigne M, Poo MM: cAMP-dependent growth cone guidance by netrin-1. Neuron. 1997, 19: 1225-1235. 10.1016/S0896-6273(00)80414-6.View ArticlePubMedGoogle Scholar
- Serafini T, Colamarino SA, Leonardo ED, Wang H, Beddington R, Skarnes WC, Tessier-Lavigne M: Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell. 1996, 87: 1001-1014. 10.1016/S0092-8674(00)81795-X.View ArticlePubMedGoogle Scholar
- Kennedy TE, Serafini T, de la Torre JR, Tessier-Lavigne M: Netrins are diffusible chemotropic factors for commissural axons in the embryonic spinal cord. Cell. 1994, 78: 425-435. 10.1016/0092-8674(94)90421-9.View ArticlePubMedGoogle Scholar
- Mitchell CB, Gasperini RJ, Small DH, Foa L: STIM1 is necessary for store-operated calcium entry in turning growth cones. J Neurochem. 2012, 122: 1155-1166. 10.1111/j.1471-4159.2012.07840.x.View ArticlePubMedGoogle Scholar
- Li Y, Jia YC, Cui K, Li N, Zheng ZY, Wang YZ, Yuan XB: Essential role of TRPC channels in the guidance of nerve growth cones by brain-derived neurotrophic factor. Nature. 2005, 434: 894-898. 10.1038/nature03477.View ArticlePubMedGoogle Scholar
- Ming G, Song H, Berninger B, Inagaki N, Tessier-Lavigne M, Poo M: Phospholipase C-gamma and phosphoinositide 3-kinase mediate cytoplasmic signaling in nerve growth cone guidance. Neuron. 1999, 23: 139-148. 10.1016/S0896-6273(00)80760-6.View ArticlePubMedGoogle Scholar
- Takei K, Shin RM, Inoue T, Kato K, Mikoshiba K: Regulation of nerve growth mediated by inositol 1,4,5-trisphosphate receptors in growth cones. Science. 1998, 282: 1705-1708.View ArticlePubMedGoogle Scholar
- Akiyama H, Matsu-ura T, Mikoshiba K, Kamiguchi H: Control of neuronal growth cone navigation by asymmetric inositol 1,4,5-trisphosphate signals. Sci Signal. 2009, 2: ra34-View ArticlePubMedGoogle Scholar
- Xie Y, Hong Y, Ma XY, Ren XR, Ackerman S, Mei L, Xiong WC: DCC-dependent phospholipase C signaling in netrin-1-induced neurite elongation. J Biol Chem. 2006, 281: 2605-2611.View ArticlePubMedGoogle Scholar
- Xie Y, Ding YQ, Hong Y, Feng Z, Navarre S, Xi CX, Zhu XJ, Wang CL, Ackerman SL, Kozlowski D, et al: Phosphatidylinositol transfer protein-alpha in netrin-1-induced PLC signalling and neurite outgrowth. Nat Cell Biol. 2005, 7: 1124-1132. 10.1038/ncb1321.View ArticlePubMedGoogle Scholar
- Yuan JP, Kim MS, Zeng W, Shin DM, Huang G, Worley PF, Muallem S: TRPC channels as STIM1-regulated SOCs. Channels (Austin). 2009, 3: 221-225. 10.4161/chan.3.4.9198.View ArticleGoogle Scholar
- Yuan JP, Zeng W, Huang GN, Worley PF, Muallem S: STIM1 heteromultimerizes TRPC channels to determine their function as store-operated channels. Nat Cell Biol. 2007, 9: 636-645. 10.1038/ncb1590.PubMed CentralView ArticlePubMedGoogle Scholar
- Kim MS, Zeng W, Yuan JP, Shin DM, Worley PF, Muallem S:Native Store-operated Ca2+Influx Requires the Channel Function of Orai1 and TRPC1.J Biol Chem. 2009, 284: 9733-9741. 10.1074/jbc.M808097200.PubMed CentralView ArticlePubMedGoogle Scholar
- Grigoriev I, Gouveia SM, van der Vaart B, Demmers J, Smyth JT, Honnappa S, Splinter D, Steinmetz MO, Putney JW, Hoogenraad CC, Akhmanova A: STIM1 is a MT-plus-end-tracking protein involved in remodeling of the ER. Curr Biol. 2008, 18: 177-182. 10.1016/j.cub.2007.12.050.PubMed CentralView ArticlePubMedGoogle Scholar
- Lefkimmiatis K, Srikanthan M, Maiellaro I, Moyer MP, Curci S, Hofer AM: Store-operated cyclic AMP signalling mediated by STIM1. Nat Cell Biol. 2009, 11: 433-442. 10.1038/ncb1850.View ArticlePubMedGoogle Scholar
- Cheng KT, Liu X, Ong HL, Swaim W, Ambudkar IS: Local Ca(2) + entry via Orai1 regulates plasma membrane recruitment of TRPC1 and controls cytosolic Ca(2) + signals required for specific cell functions. PLoS Biol. 2011, 9: e1001025-10.1371/journal.pbio.1001025.PubMed CentralView ArticlePubMedGoogle Scholar
- Ong HL, Cheng KT, Liu X, Bandyopadhyay BC, Paria BC, Soboloff J, Pani B, Gwack Y, Srikanth S, Singh BB, et al: Dynamic assembly of TRPC1-STIM1-Orai1 ternary complex is involved in store-operated calcium influx. Evidence for similarities in store-operated and calcium release-activated calcium channel components. J Biol Chem. 2007, 282: 9105-9116. 10.1074/jbc.M608942200.PubMed CentralView ArticlePubMedGoogle Scholar
- Shigetomi E, Tong X, Kwan KY, Corey DP, Khakh BS: TRPA1 channels regulate astrocyte resting calcium and inhibitory synapse efficacy through GAT-3. Nat Neurosci. 2012, 15: 70-80.View ArticleGoogle Scholar
- Shekarabi M, Kennedy TE: The netrin-1 receptor DCC promotes filopodia formation and cell spreading by activating Cdc42 and Rac1. Mol Cell Neurosci. 2002, 19: 1-17.View ArticlePubMedGoogle Scholar
- Robles E, Woo S, Gomez TM: Src-dependent tyrosine phosphorylation at the tips of growth cone filopodia promotes extension. J Neurosci. 2005, 25: 7669-7681. 10.1523/JNEUROSCI.2680-05.2005.View ArticlePubMedGoogle Scholar
- Han J, Han L, Tiwari P, Wen Z, Zheng JQ: Spatial targeting of type II protein kinase A to filopodia mediates the regulation of growth cone guidance by cAMP. J Cell Biochem Suppl. 2007, 176: 101-111.Google Scholar
- Mattila PK, Lappalainen P: Filopodia: molecular architecture and cellular functions. Nature reviews Molecular cell biology. 2008, 9: 446-454. 10.1038/nrm2406.View ArticlePubMedGoogle Scholar
- Dent EW, Gupton SL, Gertler FB: The growth cone cytoskeleton in axon outgrowth and guidance. Cold Spring Harb Perspect Biol. 2011, 3 (3): doi: 10.1101/cshperspect.a001800Google Scholar
- Gomez TM, Snow DM, Letourneau PC: Characterization of spontaneous calcium transients in nerve growth cones and their effect on growth cone migration. Neuron. 1995, 14: 1233-1246. 10.1016/0896-6273(95)90270-8.View ArticlePubMedGoogle Scholar
- Wedel B, Boyles RR, Putney JW, Bird GS: Role of the store-operated calcium entry proteins Stim1 and Orai1 in muscarinic cholinergic receptor-stimulated calcium oscillations in human embryonic kidney cells. J Physiol. 2007, 579: 679-689. 10.1113/jphysiol.2006.125641.PubMed CentralView ArticlePubMedGoogle Scholar
- Bird GS, Hwang SY, Smyth JT, Fukushima M, Boyles RR, Putney JW: STIM1 is a calcium sensor specialized for digital signaling. Curr Biol. 2009, 19: 1724-1729. 10.1016/j.cub.2009.08.022.PubMed CentralView ArticlePubMedGoogle Scholar
- Di Capite J, Ng SW, Parekh AB: Decoding of cytoplasmic Ca(2+) oscillations through the spatial signature drives gene expression. Curr Biol. 2009, 19: 853-858. 10.1016/j.cub.2009.03.063.View ArticlePubMedGoogle Scholar
- Ming GL, Wong ST, Henley J, Yuan XB, Song HJ, Spitzer NC, Poo MM: Adaptation in the chemotactic guidance of nerve growth cones. Nature. 2002, 417: 411-418. 10.1038/nature745.View ArticlePubMedGoogle Scholar
- Harland RM: In situ hybridization: an improved whole-mount method for Xenopus embryos. Methods Cell Biol. 1991, 36: 685-695.View ArticlePubMedGoogle Scholar
- Lohof AM, Quillan M, Dan Y, Poo MM: Asymmetric modulation of cytosolic cAMP activity induces growth cone turning. J Neurosci. 1992, 12: 1253-1261.PubMedGoogle Scholar
- Zheng JQ, Felder M, Connor JA, Poo MM: Turning of nerve growth cones induced by neurotransmitters. Nature. 1994, 368: 140-144. 10.1038/368140a0.View ArticlePubMedGoogle Scholar
- Rivas RJ, Burmeister DW, Goldberg DJ: Rapid effects of laminin on the growth cone. Neuron. 1992, 8: 107-115. 10.1016/0896-6273(92)90112-Q.View ArticlePubMedGoogle Scholar
- Hopker VH, Shewan D, Tessier-Lavigne M, Poo M, Holt C: Growth-cone attraction to netrin-1 is converted to repulsion by laminin-1. Nature. 1999, 401: 69-73. 10.1038/43441.View ArticlePubMedGoogle Scholar
- Gomez TM, Spitzer NC: In vivo regulation of axon extension and pathfinding by growth-cone calcium transients. Nature. 1999, 397: 350-355. 10.1038/16927.View ArticlePubMedGoogle Scholar
- Phelps PE, Alijani A, Tran TS: Ventrally located commissural neurons express the GABAergic phenotype in developing rat spinal cord. J Comp Neurol. 1999, 409: 285-298. 10.1002/(SICI)1096-9861(19990628)409:2<285::AID-CNE9>3.0.CO;2-7.View ArticlePubMedGoogle Scholar
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