Calcium arising through release from intracellular stores and from influx across the plasma membrane is essential for signalling by specific guidance cues and by factors that inhibit axon regeneration. The mediators of calcium influx in these cases are largely unknown. Transient receptor potential channels (TRPCs) belong to a superfamily of Ca 2+ -permeable, receptoroperated channels that have important roles in sensing and responding to changes in the local environment. Here we report that XTRPC1, a Xenopus homolog of mammalian TRPC1, is required for proper growth cone turning responses of Xenopus spinal neurons to microscopic gradients of netrin-1, brain-derived neurotrophic factor and myelin-associated glycoprotein, but not to semaphorin 3A. Furthermore, XTRPC1 is required for midline guidance of axons of commissural interneurons in the developing Xenopus spinal cord. Thus, members of the TRPC family may serve as a key mediator for the Ca 2+ influx that regulates axon guidance during development and inhibits axon regeneration in adulthood.Axons are guided to their targets in the developing nervous system by diffusible and bound cues that either attract or repel the growing tip of an axon, the growth cone [1][2][3][4] . Once neuronal circuits are formed, the ability of axons to regenerate after injury or disease in the mature mammalian CNS is extremely limited, largely because of the presence of inhibitory factors [5][6][7][8][9][10] . During the last decade, an array of evolutionarily conserved guidance cues and © 2005 Nature Publishing Group Correspondence should be addressed to G.L.M. (gming1@bs.jhmi.edu). Note: Supplementary information is available on the Nature Neuroscience website.
COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests.
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NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript their receptors have been identified and have been shown to be involved in axon guidance during development and in axon regeneration in the adult central nervous system [1][2][3]6 . How specific guidance signals are transduced from receptor activation to rearrangement of cytoskeleton within the neuronal growth cone is just beginning to be elucidated [1][2][3][4]11,12 . One of the initial signal transduction mechanisms that triggers the growth cone responses to a large number of guidance cues and inhibitory factors associated with myelin is an increase in cytosolic Ca 2+ , arising from both intracellular store release and influx across the plasma membrane 5,7,[13][14][15][16][17] . Notably, different patterns of Ca 2+ elevation trigger differential attractive and repulsive turning responses of the growth cone 13,18 . While previous studies have demonstrated the essential role of Ca 2+ signalling in axon guidance and regeneration both in vitro and in vivo 5,7,[11][12][13][15][16][17][18][19][20][21][22][23][24] , it is unknown how initial Ca 2+ mobilization from intracellular stores is coupled to sustained Ca 2+ influx from the extr...