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The Journal of Neuroscience, July 15, 2009, 29(28):8946-8959; doi:10.1523/JNEUROSCI.2030-09.2009

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Cellular/Molecular
Regulation of Early Neurite Morphogenesis by the Na⁺/H⁺ Exchanger NHE1

Wun-Chey Sin,^1 * David M. Moniz,^1 * Mark A. Ozog,¹ Jessica E. Tyler,¹ Masayuki Numata,² and John Church^1,3

Departments of ¹Cellular and Physiological Sciences and ²Biochemistry and Molecular Biology and ³Graduate Program in Cell and Developmental Biology, The University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

Correspondence should be addressed to John Church, Department of Cellular and Physiological Sciences, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 123, Canada. Email: jchurch{at}interchange.ubc.ca

The ubiquitously expressed Na⁺/H⁺ exchanger NHE1 plays an important role in regulating polarized membrane protrusion and directional motility in non-neuronal cells. Using NGF-differentiated PC12 cells and murine neocortical neurons in vitro, we now show that NHE1 plays a role in regulating early neurite morphogenesis. NHE1 was expressed in growth cones in which it gave rise to an elevated intracellular pH in actively extending neurites. The NHE1 inhibitor cariporide reversibly reduced growth cone filopodia number and the formation and elongation of neurites, especially branches, whereas the transient overexpression of full-length NHE1, but not NHE1 mutants deficient in either ion translocation activity or actin cytoskeletal anchoring, elicited opposite effects. In addition, compared with neocortical neurons obtained from wild-type littermates, neurons isolated from NHE1-null mice exhibited reductions in early neurite outgrowth, an effect that was rescued by overexpression of full-length NHE1 but not NHE1 mutants. Finally, the growth-promoting effects of netrin-1, but not BDNF or IGF-1, were markedly reduced by cariporide in wild-type neocortical neurons and were not observed in NHE1-null neurons. Although netrin-1 failed to increase growth cone intracellular pH or Na⁺/H⁺ exchange activity, netrin-1-induced increases in early neurite outgrowth were restored in NHE1-null neurons transfected with full-length NHE1 but not an ion translocation-deficient mutant. Collectively, the results indicate that NHE1 participates in the regulation of early neurite morphogenesis and identify a novel role for NHE1 in the promotion of early neurite outgrowth by netrin-1.

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Received April 29, 2009; accepted June 3, 2009.

Correspondence should be addressed to John Church, Department of Cellular and Physiological Sciences, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 123, Canada. Email: jchurch{at}interchange.ubc.ca

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