title: BDNF profoundly and specifically increases KCNQ4 expression in neurons derived from embryonic stem cells.
abstract: Neurons resembling the spiral ganglion neurons (SGNs) of the auditory nerve can be generated from embryonic stem cells through induced overexpression of the transcription factor Neurogenin-1 (Neurog1). While recapitulating this developmental pathway produces glutamatergic, bipolar neurons reminiscent of SGNs, these neurons are functionally immature, being characterized by a depolarized resting potential and limited excitability. We explored the effects of two neurotrophins known to be present in the inner ear, brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), on the electrophysiology of neurons following Neurog1 induction. Our data reveal a significant reduction in resting membrane potential (RMP) following neurotrophin exposure, with BDNF producing a more robust effect than NT-3. This effect was accompanied by a profound and specific upregulation of the KCNQ4 subtype, where a 9-fold increase was observed with quantitative PCR. The other neuronally expressed KCNQ subtypes (2, 3, and 5) exhibited upregulation which was 3-fold or less in magnitude. Quantitative immunohistochemistry confirmed the increase in KCNQ4 expression at the protein level. The present data show a novel link between BDNF and KCNQ4 expression, yielding insight into the restricted expression pattern of a channel known to play special roles in setting the resting potential of auditory cells and in the etiology of progressive high-frequency hearing loss.
authors.affiliation: The University of Michigan, Ann Arbor, MI 48109, USA. erinfred@umich.edu
authors.forename: Erin K
authors.initials: EK
authors.lastname: Purcell
authors.forename: Amy
authors.initials: A
authors.lastname: Yang
authors.forename: Liqian
authors.initials: L
authors.lastname: Liu
authors.forename: J Matthew
authors.initials: JM
authors.lastname: Velkey
authors.forename: Marti M
authors.initials: MM
authors.lastname: Morales
authors.forename: R Keith
authors.initials: RK
authors.lastname: Duncan
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002454:Cell Differentiation; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051656:KCNQ Potassium Channels / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D020933:Neurotrophin 3 / Q000494:pharmacology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019208:Brain-Derived Neurotrophic Factor; D051656:KCNQ Potassium Channels; D009419:Nerve Tissue Proteins; D020933:Neurotrophin 3; C492167:Kcnq4 protein, mouse; C486336:Neurog1 protein, mouse