title: Christianson syndrome protein NHE6 modulates TrkB endosomal signaling required for neuronal circuit development.
abstract: Neuronal arborization is regulated by cell-autonomous and nonautonomous mechanisms including endosomal signaling via BDNF/TrkB. The endosomal Na⁺/H⁺ exchanger 6 (NHE6) is mutated in a new autism-related disorder. NHE6 functions to permit proton leak from endosomes, yet the mechanisms causing disease are unknown. We demonstrate that loss of NHE6 results in overacidification of the endosomal compartment and attenuated TrkB signaling. Mouse brains with disrupted NHE6 display reduced axonal and dendritic branching, synapse number, and circuit strength. Site-directed mutagenesis shows that the proton leak function of NHE6 is required for neuronal arborization. We find that TrkB receptor colocalizes to NHE6-associated endosomes. TrkB protein and phosphorylation are reduced in NHE6 mutant neurons in response to BDNF signaling. Finally, exogenous BDNF rescues defects in neuronal arborization. We propose that NHE6 mutation leads to circuit defects that are in part due to impoverished neuronal arborization that may be treatable by enhanced TrkB signaling.
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, and Institute for Brain Science, Brown University, Laboratory for Molecular Medicine, 70 Ship Street, Providence, RI 02903, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ouyang
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, and Institute for Brain Science, Brown University, Laboratory for Molecular Medicine, 70 Ship Street, Providence, RI 02903, USA.
authors.forename: Sofia B
authors.initials: SB
authors.lastname: Lizarraga
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, and Institute for Brain Science, Brown University, Laboratory for Molecular Medicine, 70 Ship Street, Providence, RI 02903, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, and Institute for Brain Science, Brown University, Laboratory for Molecular Medicine, 70 Ship Street, Providence, RI 02903, USA.
authors.forename: Unikora
authors.initials: U
authors.lastname: Yang
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, and Institute for Brain Science, Brown University, Laboratory for Molecular Medicine, 70 Ship Street, Providence, RI 02903, USA.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Gong
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, and Institute for Brain Science, Brown University, Laboratory for Molecular Medicine, 70 Ship Street, Providence, RI 02903, USA.
authors.forename: Debra
authors.initials: D
authors.lastname: Ellisor
authors.affiliation: Departments of Molecular Pharmacology, Physiology and Biotechnology, and Neuroscience, Brown University, Providence, Rhode Island 02912, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Kauer
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, and Institute for Brain Science, Brown University, Laboratory for Molecular Medicine, 70 Ship Street, Providence, RI 02903, USA.|Developmental Disorders Genetics Research Program, Emma Pendleton Bradley Hospital and Department of Psychiatry and Human Behavior, Brown University Medical School, 1011 Veteran Memorial Pkwy., East Providence, RI 02915, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Morrow
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002478:Cells, Cultured; D003712:Dendrites / Q000502:physiology; D011992:Endosomes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009415:Nerve Net / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D020813:Receptor, trkB / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics* / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C503961:NHE6 protein, mouse; D017923:Sodium-Hydrogen Exchangers; D020813:Receptor, trkB
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