A critical role for STIM1 in filopodial calcium entry and axon guidance

BACKGROUND: Stromal interaction molecule 1 (STIM1), a Ca(2+) sensor in the endoplasmic reticulum, regulates store-operated Ca(2+) entry (SOCE) that is essential for Ca(2+) 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. RESULTS: We report that STIM1 and transient receptor potential channel 1 (TRPC1)-dependent SOCE operates in Xenopus spinal growth cones to regulate Ca(2+) 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 Ca(2+) transients in the growth cone. Disruption of STIM1 function abolished filopodial Ca(2+) transients and impaired Ca(2+)-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. CONCLUSIONS: Our data demonstrate that STIM1/TRPC1-dependent SOCE plays an essential role in generating spatiotemporal Ca(2+) signals that mediate guidance responses of nerve growth cones.