title: The spatiotemporal segregation of GAD forms defines distinct GABA signaling functions in the developing mouse olfactory system and provides novel insights into the origin and migration of GnRH neurons.
abstract: Gamma-aminobutyric acid (GABA) has a dual role as an inhibitory neurotransmitter in the adult central nervous system (CNS) and as a signaling molecule exerting largely excitatory actions during development. The rate-limiting step of GABA synthesis is catalyzed by two glutamic acid decarboxylase isoforms GAD65 and GAD67 coexpressed in the GABAergic neurons of the CNS. Here we report that the two GADs show virtually nonoverlapping expression patterns consistent with distinct roles in the developing peripheral olfactory system. GAD65 is expressed exclusively in undifferentiated neuronal progenitors confined to the proliferative zones of the sensory vomeronasal and olfactory epithelia In contrast GAD67 is expressed in a subregion of the nonsensory epithelium/vomeronasal organ epithelium containing the putative Gonadotropin-releasing hormone (GnRH) progenitors and GnRH neurons migrating from this region through the frontonasal mesenchyme into the basal forebrain. Only GAD67+, but not GAD65+ cells accumulate detectable GABA. We further demonstrate that GAD67 and its embryonic splice variant embryonic GAD (EGAD) concomitant with GnRH are dynamically regulated during GnRH neuronal migration in vivo and in two immortalized cell lines representing migratory (GN11) and postmigratory (GT1-7) stage GnRH neurons, respectively. Analysis of GAD65/67 single and double knock-out embryos revealed that the two GADs play complementary (inhibitory) roles in GnRH migration ultimately modulating the speed and/or direction of GnRH migration. Our results also suggest that GAD65 and GAD67/EGAD characterized by distinct subcellular localization and kinetics have disparate functions during olfactory system development mediating proliferative and migratory responses putatively through specific subcellular GABA pools.
authors.affiliation: Division of Medical Gene Technology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary; Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Vastagh
authors.forename: Marija
authors.initials: M
authors.lastname: Schwirtlich
authors.forename: Andrea
authors.initials: A
authors.lastname: Kwakowsky
authors.forename: Ferenc
authors.initials: F
authors.lastname: Erdélyi
authors.forename: Frank L
authors.initials: FL
authors.lastname: Margolis
authors.forename: Yuchio
authors.initials: Y
authors.lastname: Yanagawa
authors.forename: Zoya
authors.initials: Z
authors.lastname: Katarova
authors.forename: Gábor
authors.initials: G
authors.lastname: Szabó
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology / Q000254:growth & development; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D004848:Epithelium / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005968:Glutamate Decarboxylase / Q000172:deficiency / Q000235:genetics*; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology*; D009831:Olfactory Mucosa / Q000166:cytology; D009833:Olfactory Pathways / Q000196:embryology / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D007987:Gonadotropin-Releasing Hormone; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2
keywords: GAD forms; GnRH; cell migration; gamma-aminobutyric acid; olfactory development