Editors' ChoiceNeuroscience

Pacing Acidification for Neural Development

Sci. Signal.  08 Oct 2013:
Vol. 6, Issue 296, pp. ec244
DOI: 10.1126/scisignal.2004790

Endosomes undergo a maturation process during which they are gradually acidified and fuse with lysosomes. Although some of the membrane-embedded and membrane-associated constituents of endosomes are destined for lysosomal degradation, some components of early endosomes are recycled, and some activated receptors continue to signal from early endosomes. Ouyang et al. report that the endosomal Na+/H+ exchanger NHE6 was required for endosomal signaling by TrkB, the receptor for brain-derived neurotrophic factor (BDNF), and for proper neuronal arborization. Mutations in NHE6 are associated with various neurodevelopmental disorders, including Christianson syndrome, autism, and epilepsy. NHE exchanges Na+ or K+ for H+ to allow protons (H+) to leak out of the endosome, thus counteracting endosomal acidification. NHE6 was localized to endosomes at sites of axon and dendrite outgrowth in the brains of mouse embryos and in hippocampal neurons isolated from mouse embryos. NHE6–/– hippocampal axons and dendrites showed reduced branching both in vivo and in culture. Wild-type NHE6, but not a mutant version lacking cation exchanger activity, rescued the reduced branching phenotype in cultured hippocampal neurons. Electrophysiological experiments using hippocampal slices were consistent with NHE6–/– mutants having a reduced number of active synapses compared with wild-type mice, and cultured NHE6–/– hippocampal neurons showed fewer mature dendritic spines than did wild-type cells. Labeling with a low pH–responsive dye showed that acidic endosomes were distributed close to sites of axon and dendrite outgrowth in NHE6–/– neurons, whereas low-pH endosomes were closer to the cell body in wild-type neurons. Endosomes in neurons expressing a mutant NHE6 lacking cation exchanger activity were also more acidic than endosomes in neurons expressing wild-type NHE6. BDNF-TrkB signaling is important for neuronal arborization; upon binding to BDNF, TrkB is internalized and signals from endosomes. NHE6 and TrkB colocalized to endosomes near sites of growing axons and dendrites. Upon exposure to exogenous BDNF, NHE6–/– neurons showed reduced abundance of both TrkB and activated TrkB (phosphorylated Trk) compared with wild-type neurons. The reduction in phosphorylated Trk abundance in response to BDNF was rescued by treating NHE6–/– neurons with an inhibitor of acid-activated proteases before BDNF application. These results are consistent with excessive acidification of early endosomes, which attenuated BDNF-TrkB signaling by increasing the degradation of TrkB. Therefore, NHE6 likely contributes to proper development of neuronal circuitry by slowing endosomal acidification, thus prolonging the duration of BDNF-TrkB signaling. Commentary by Yap and Winckler highlights the relationship between endolysosomal biology and neural development.

Q. Ouyang, S. B. Lizarraga, M. Schmidt, U. Yang, J. Gong, D. Ellisor, J. A. Kauer, E. M. Morrow, Christianson syndrome protein NHE6 modulates TrkB endosomal signaling required for neuronal circuit development. Neuron 80, 97–112 (2013). [PubMed]

C. C. Yap, B. Winckler, Acid indigestion in the endosome: Linking signaling dysregulation to neurodevelopmental disorders. Neuron 80, 4–6 (2013). [PubMed]