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
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2015
Authors
Vastagh, CsabaSchwirtlich, Marija
Kwakowsky, Andrea
Erdelyi, Ferenc
Margolis, Frank L.
Yanagawa, Yuchio
Katarova, Zoya
Szabo, Gabor
Article (Published version)
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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.
Keywords:
olfactory development / GnRH / gamma-aminobutyric acid / GAD forms / cell migrationSource:
Developmental Neurobiology, 2015, 75, 3, 249-270Publisher:
- Wiley, Hoboken
Funding / projects:
- Hungarian National Grant Agency (OTKA) [38098]
- Studying signal transduction pathways and epigenetic mechanisms that control human SOX genes expression: further insight into their roles in cell fate determination and differentiation (RS-MESTD-Basic Research (BR or ON)-173051)
- NIH [DC03112]
DOI: 10.1002/dneu.22222
ISSN: 1932-8451
PubMed: 25125027
WoS: 000349612800003
Scopus: 2-s2.0-84922781290
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Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Vastagh, Csaba AU - Schwirtlich, Marija AU - Kwakowsky, Andrea AU - Erdelyi, Ferenc AU - Margolis, Frank L. AU - Yanagawa, Yuchio AU - Katarova, Zoya AU - Szabo, Gabor PY - 2015 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/898 AB - 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. PB - Wiley, Hoboken T2 - Developmental Neurobiology T1 - 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 EP - 270 IS - 3 SP - 249 VL - 75 DO - 10.1002/dneu.22222 ER -
@article{ author = "Vastagh, Csaba and Schwirtlich, Marija and Kwakowsky, Andrea and Erdelyi, Ferenc and Margolis, Frank L. and Yanagawa, Yuchio and Katarova, Zoya and Szabo, Gabor", year = "2015", 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.", publisher = "Wiley, Hoboken", journal = "Developmental Neurobiology", 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", pages = "270-249", number = "3", volume = "75", doi = "10.1002/dneu.22222" }
Vastagh, C., Schwirtlich, M., Kwakowsky, A., Erdelyi, F., Margolis, F. L., Yanagawa, Y., Katarova, Z.,& Szabo, G.. (2015). 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. in Developmental Neurobiology Wiley, Hoboken., 75(3), 249-270. https://doi.org/10.1002/dneu.22222
Vastagh C, Schwirtlich M, Kwakowsky A, Erdelyi F, Margolis FL, Yanagawa Y, Katarova Z, Szabo G. 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. in Developmental Neurobiology. 2015;75(3):249-270. doi:10.1002/dneu.22222 .
Vastagh, Csaba, Schwirtlich, Marija, Kwakowsky, Andrea, Erdelyi, Ferenc, Margolis, Frank L., Yanagawa, Yuchio, Katarova, Zoya, Szabo, Gabor, "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" in Developmental Neurobiology, 75, no. 3 (2015):249-270, https://doi.org/10.1002/dneu.22222 . .