title: Knockdown of Nav1.6a Na+ channels affects zebrafish motoneuron development.
abstract: In addition to rapid signaling, electrical activity provides important cues to developing neurons. Electrical activity relies on the function of several different types of voltage-gated ion channels. Whereas voltage-gated Ca2+ channel activity regulates several aspects of neuronal differentiation, much less is known about developmental roles of voltage-gated Na+ channels, essential mediators of electrical signaling. Here, we focus on the zebrafish Na+ channel isotype, Nav1.6a, which is encoded by the scn8a gene. A restricted set of spinal neurons, including dorsal sensory Rohon-Beard cells, two motoneuron subtypes with different axonal trajectories, express scn8a during embryonic development. CaP, an early born primary motoneuron subtype with ventrally projecting axons expresses scn8a, as does a class of secondary motoneurons with axons that project dorsally. To test for developmental roles of scn8a, we knocked down Nav1.6a protein using antisense morpholinos. Na+ channel protein and current amplitudes were reduced in neurons that express scn8a. Furthermore, Nav1.6a knockdown altered axonal morphologies of some but not all motoneurons. Dorsally projecting secondary motoneurons express scn8a and displayed delayed axonal outgrowth. By contrast, CaP axons developed normally, despite expression of the gene. Surprisingly, ventrally projecting secondary motoneurons, a population in which scn8a was not detected, displayed aberrant axonal morphologies. Mosaic analysis indicated that effects on ventrally projecting secondary motoneurons were non cell-autonomous. Thus, voltage-gated Na+ channels play cell-autonomous and non cell-autonomous roles during neuronal development.
authors.affiliation: Department of Physiology and Biophysics, 8307 University of Colorado Denver and Health Sciences Center, Aurora, CO 80045, USA.
authors.forename: Ricardo H
authors.initials: RH
authors.lastname: Pineda
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Svoboda
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Wright
authors.forename: Alison D
authors.initials: AD
authors.lastname: Taylor
authors.forename: Alicia E
authors.initials: AE
authors.lastname: Novak
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Gamse
authors.forename: Judith S
authors.initials: JS
authors.lastname: Eisen
authors.forename: Angeles B
authors.initials: AB
authors.lastname: Ribera
mesh_terms: D000818:Animals; D001369:Axons / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure*; D002470:Cell Survival; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000378:metabolism; D047108:Embryonic Development / Q000187:drug effects / Q000235:genetics; D009046:Motor Neurons / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D062557:NAV1.6 Voltage-Gated Sodium Channel; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D062557:NAV1.6 Voltage-Gated Sodium Channel; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D015222:Sodium Channels; D029961:Zebrafish Proteins; C515010:scn8aa protein, zebrafish