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The Na⁺/H⁺ exchanger NHE1 plays a permissive role in regulating early neurite morphogenesis

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dc.contributor.author Moniz, David Matthew
dc.date.accessioned 2008-11-24T18:01:58Z
dc.date.available 2008-11-24T18:01:58Z
dc.date.copyright 2008 en
dc.date.issued 2008-11-24T18:01:58Z
dc.identifier.uri http://hdl.handle.net/2429/2810
dc.description.abstract The ubiquitously expressed plasma membrane Na⁺/H⁺ exchanger isoform 1 (NHE1) plays an important role in directed cell migration in non-neuronal cells, an effect which requires both the ion translocation and actin cytoskeleton anchoring functions of the protein. In the present study, an analogous role for NHE1 as a modulator of neurite outgrowth was evaluated in vitro utilizing NGF-differentiated PC12 cells as well as mouse neocortical neurons in primary culture. Examined at 3 d.i.v., endogenous NHE1 was found to be expressed in growth cones, where it gave rise to an elevated intracellular pH in actively-extending neurites. Application of the NHE inhibitor cariporide at an NHE1-selective concentration (1 μM) resulted in reductions in neurite extension and elaboration while application of 100 μM cariporide, to inhibit all known plasmalemmal NHE isoforms, failed to exert additional inhibitory effects, suggesting a dominant role for the NHE1 isoform in modulating neurite outgrowth. In addition, whereas transient overexpression of full-length NHE1 enhanced neurite outgrowth in a cariporide-sensitive manner in both NGF-differentiated PC12 cells and WT neocortical neurons, neurite outgrowth was reduced in NGF-differentiated PC12 cells overexpressing NHE1 mutants deficient in either ion translocation activity or actin cytoskeleton anchoring, suggesting that both functional domains of NHE1 are important for modulating neurite elaboration. A role for NHE1 in modulating neurite outgrowth was confirmed in neocortical neurons obtained from NHE1-/- mice which displayed reduced neurite outgrowth when compared to neurons obtained from their NHE1⁺/⁺ littermates. Further, neurite outgrowth in NHE1-/- neurons was rescued by transient overexpression of full-length NHE1 but not with mutant NHE1 constructs again suggesting that both functional domains of NHE1 are important for modulating neurite outgrowth. Finally, the growth promoting effects of netrin-1 but not BDNF or IGF-1 were abolished by cariporide in WT neocortical neurons and while both BDNF and IGF-1 were able to promote neurite outgrowth in NHE1-/- neurons, netrin-1 was unable to elicit this effect. Taken together, these results indicate that NHE1 is a permissive regulator of early neurite morphogenesis and also plays a novel role in netrin-1-stimulated neurite outgrowth. en
dc.format.extent 2387865 bytes
dc.format.mimetype application/pdf
dc.language.iso eng en
dc.publisher University of British Columbia
dc.subject Neurite outgrowth en
dc.subject Axon en
dc.subject Dendrite en
dc.subject Nhe1 en
dc.subject Na⁺/h⁺ exchange en
dc.subject Intracellular ph en
dc.title The Na⁺/H⁺ exchanger NHE1 plays a permissive role in regulating early neurite morphogenesis en
dc.type Electronic Thesis or Dissertation
dc.degree.name Master of Science - MSc en
dc.degree.discipline Cell and Developmental Biology en
dc.degree.grantor University of British Columbia
dc.date.graduation 2009-05 en
dc.degree.campus UBCV en

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