Clustered Protocadherins Are Required for Building Functional Neural Circuits
Neuronal identity is generated by the cell-surface expression of clustered protocadherin (Pcdh) isoforms. In mice, 58 isoforms from three gene clusters, Pcdhα, Pcdhβ, and Pcdhγ, are differentially expressed in neurons. Since cis-heteromeric Pcdh oligomers on the cell surface interact homophilically...
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Language: | English |
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Frontiers Media S.A.
2017-04-01
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Series: | Frontiers in Molecular Neuroscience |
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Online Access: | http://journal.frontiersin.org/article/10.3389/fnmol.2017.00114/full |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Takeshi Yagi Takeshi Yagi Sonoko Hasegawa Sonoko Hasegawa Hiroaki Kobayashi Hiroaki Kobayashi Makiko Kumagai Makiko Kumagai Hiroshi Nishimaru Etsuko Tarusawa Hiro Kanda Hiro Kanda Makoto Sanbo Yumiko Yoshimura Masumi Hirabayashi Takahiro Hirabayashi Takahiro Hirabayashi |
spellingShingle |
Takeshi Yagi Takeshi Yagi Sonoko Hasegawa Sonoko Hasegawa Hiroaki Kobayashi Hiroaki Kobayashi Makiko Kumagai Makiko Kumagai Hiroshi Nishimaru Etsuko Tarusawa Hiro Kanda Hiro Kanda Makoto Sanbo Yumiko Yoshimura Masumi Hirabayashi Takahiro Hirabayashi Takahiro Hirabayashi Clustered Protocadherins Are Required for Building Functional Neural Circuits Frontiers in Molecular Neuroscience genome engineering synapse synchronous activity homophilic interaction locomotion brainstem reticular formation |
author_facet |
Takeshi Yagi Takeshi Yagi Sonoko Hasegawa Sonoko Hasegawa Hiroaki Kobayashi Hiroaki Kobayashi Makiko Kumagai Makiko Kumagai Hiroshi Nishimaru Etsuko Tarusawa Hiro Kanda Hiro Kanda Makoto Sanbo Yumiko Yoshimura Masumi Hirabayashi Takahiro Hirabayashi Takahiro Hirabayashi |
author_sort |
Takeshi Yagi |
title |
Clustered Protocadherins Are Required for Building Functional Neural Circuits |
title_short |
Clustered Protocadherins Are Required for Building Functional Neural Circuits |
title_full |
Clustered Protocadherins Are Required for Building Functional Neural Circuits |
title_fullStr |
Clustered Protocadherins Are Required for Building Functional Neural Circuits |
title_full_unstemmed |
Clustered Protocadherins Are Required for Building Functional Neural Circuits |
title_sort |
clustered protocadherins are required for building functional neural circuits |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Molecular Neuroscience |
issn |
1662-5099 |
publishDate |
2017-04-01 |
description |
Neuronal identity is generated by the cell-surface expression of clustered protocadherin (Pcdh) isoforms. In mice, 58 isoforms from three gene clusters, Pcdhα, Pcdhβ, and Pcdhγ, are differentially expressed in neurons. Since cis-heteromeric Pcdh oligomers on the cell surface interact homophilically with that in other neurons in trans, it has been thought that the Pcdh isoform repertoire determines the binding specificity of synapses. We previously described the cooperative functions of isoforms from all three Pcdh gene clusters in neuronal survival and synapse formation in the spinal cord. However, the neuronal loss and the following neonatal lethality prevented an analysis of the postnatal development and characteristics of the clustered-Pcdh-null (Δαβγ) neural circuits. Here, we used two methods, one to generate the chimeric mice that have transplanted Δαβγ neurons into mouse embryos, and the other to generate double mutant mice harboring null alleles of both the Pcdh gene and the proapoptotic gene Bax to prevent neuronal loss. First, our results showed that the surviving chimeric mice that had a high contribution of Δαβγ cells exhibited paralysis and died in the postnatal period. An analysis of neuronal survival in postnatally developing brain regions of chimeric mice clarified that many Δαβγ neurons in the forebrain were spared from apoptosis, unlike those in the reticular formation of the brainstem. Second, in Δαβγ/Bax null double mutants, the central pattern generator (CPG) for locomotion failed to create a left-right alternating pattern even in the absence of neurodegeneraton. Third, calcium imaging of cultured hippocampal neurons showed that the network activity of Δαβγ neurons tended to be more synchronized and lost the variability in the number of simultaneously active neurons observed in the control network. Lastly, a comparative analysis for trans-homophilic interactions of the exogenously introduced single Pcdh-γA3 isoforms between the control and the Δαβγ neurons suggested that the isoform-specific trans-homophilic interactions require a complete match of the expressed isoform repertoire at the contacting sites between interactive neurons. These results suggested that combinations of clustered Pcdh isoforms are required for building appropriate neural circuits. |
topic |
genome engineering synapse synchronous activity homophilic interaction locomotion brainstem reticular formation |
url |
http://journal.frontiersin.org/article/10.3389/fnmol.2017.00114/full |
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doaj-dd9536cac1064b8ca40104db51a0cf762020-11-24T20:59:12ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992017-04-011010.3389/fnmol.2017.00114256917Clustered Protocadherins Are Required for Building Functional Neural CircuitsTakeshi Yagi0Takeshi Yagi1Sonoko Hasegawa2Sonoko Hasegawa3Hiroaki Kobayashi4Hiroaki Kobayashi5Makiko Kumagai6Makiko Kumagai7Hiroshi Nishimaru8Etsuko Tarusawa9Hiro Kanda10Hiro Kanda11Makoto Sanbo12Yumiko Yoshimura13Masumi Hirabayashi14Takahiro Hirabayashi15Takahiro Hirabayashi16KOKORO-Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka UniversitySuita, JapanJapan Science and Technology Agency-Core Research for Evolutional Science and Technology, CREST, Osaka UniversitySuita, Osaka, JapanKOKORO-Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka UniversitySuita, JapanJapan Science and Technology Agency-Core Research for Evolutional Science and Technology, CREST, Osaka UniversitySuita, Osaka, JapanKOKORO-Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka UniversitySuita, JapanJapan Science and Technology Agency-Core Research for Evolutional Science and Technology, CREST, Osaka UniversitySuita, Osaka, JapanKOKORO-Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka UniversitySuita, JapanJapan Science and Technology Agency-Core Research for Evolutional Science and Technology, CREST, Osaka UniversitySuita, Osaka, JapanSystem Emotional Science, Graduate School of Medicine, University of ToyamaToyama, JapanSection of Visual Information Processing, National Institute for Physiological Sciences, National Institutes of Natural SciencesOkazaki, JapanKOKORO-Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka UniversitySuita, JapanJapan Science and Technology Agency-Core Research for Evolutional Science and Technology, CREST, Osaka UniversitySuita, Osaka, JapanSection of Mammalian Transgenesis, Center for Genetic Analysis of Behavior, National Institute for Physiological SciencesOkazaki, JapanSection of Visual Information Processing, National Institute for Physiological Sciences, National Institutes of Natural SciencesOkazaki, JapanSection of Mammalian Transgenesis, Center for Genetic Analysis of Behavior, National Institute for Physiological SciencesOkazaki, JapanKOKORO-Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka UniversitySuita, JapanJapan Science and Technology Agency-Core Research for Evolutional Science and Technology, CREST, Osaka UniversitySuita, Osaka, JapanNeuronal identity is generated by the cell-surface expression of clustered protocadherin (Pcdh) isoforms. In mice, 58 isoforms from three gene clusters, Pcdhα, Pcdhβ, and Pcdhγ, are differentially expressed in neurons. Since cis-heteromeric Pcdh oligomers on the cell surface interact homophilically with that in other neurons in trans, it has been thought that the Pcdh isoform repertoire determines the binding specificity of synapses. We previously described the cooperative functions of isoforms from all three Pcdh gene clusters in neuronal survival and synapse formation in the spinal cord. However, the neuronal loss and the following neonatal lethality prevented an analysis of the postnatal development and characteristics of the clustered-Pcdh-null (Δαβγ) neural circuits. Here, we used two methods, one to generate the chimeric mice that have transplanted Δαβγ neurons into mouse embryos, and the other to generate double mutant mice harboring null alleles of both the Pcdh gene and the proapoptotic gene Bax to prevent neuronal loss. First, our results showed that the surviving chimeric mice that had a high contribution of Δαβγ cells exhibited paralysis and died in the postnatal period. An analysis of neuronal survival in postnatally developing brain regions of chimeric mice clarified that many Δαβγ neurons in the forebrain were spared from apoptosis, unlike those in the reticular formation of the brainstem. Second, in Δαβγ/Bax null double mutants, the central pattern generator (CPG) for locomotion failed to create a left-right alternating pattern even in the absence of neurodegeneraton. Third, calcium imaging of cultured hippocampal neurons showed that the network activity of Δαβγ neurons tended to be more synchronized and lost the variability in the number of simultaneously active neurons observed in the control network. Lastly, a comparative analysis for trans-homophilic interactions of the exogenously introduced single Pcdh-γA3 isoforms between the control and the Δαβγ neurons suggested that the isoform-specific trans-homophilic interactions require a complete match of the expressed isoform repertoire at the contacting sites between interactive neurons. These results suggested that combinations of clustered Pcdh isoforms are required for building appropriate neural circuits.http://journal.frontiersin.org/article/10.3389/fnmol.2017.00114/fullgenome engineeringsynapsesynchronous activityhomophilic interactionlocomotionbrainstem reticular formation |