An autism-associated variant of Epac2 reveals a role for Ras/Epac2 signaling in controlling basal dendrite maintenance in mice.

The architecture of dendritic arbors determines circuit connectivity, receptive fields, and computational properties of neurons, and dendritic structure is impaired in several psychiatric disorders. While apical and basal dendritic compartments of pyramidal neurons are functionally specialized and d...

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Autores principales:	Deepak P Srivastava, Kevin M Woolfrey, Kelly A Jones, Charles T Anderson, Katharine R Smith, Theron A Russell, Hyerin Lee, Marina V Yasvoina, David L Wokosin, P Hande Ozdinler, Gordon M G Shepherd, Peter Penzes
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/82bebeeb8c44423d9a906dbfb32001e3
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spelling	oai:doaj.org-article:82bebeeb8c44423d9a906dbfb32001e32021-11-18T05:36:36ZAn autism-associated variant of Epac2 reveals a role for Ras/Epac2 signaling in controlling basal dendrite maintenance in mice.1544-91731545-788510.1371/journal.pbio.1001350https://doaj.org/article/82bebeeb8c44423d9a906dbfb32001e32012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22745599/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885The architecture of dendritic arbors determines circuit connectivity, receptive fields, and computational properties of neurons, and dendritic structure is impaired in several psychiatric disorders. While apical and basal dendritic compartments of pyramidal neurons are functionally specialized and differentially regulated, little is known about mechanisms that selectively maintain basal dendrites. Here we identified a role for the Ras/Epac2 pathway in maintaining basal dendrite complexity of cortical neurons. Epac2 is a guanine nucleotide exchange factor (GEF) for the Ras-like small GTPase Rap, and it is highly enriched in the adult mouse brain. We found that in vivo Epac2 knockdown in layer 2/3 cortical neurons via in utero electroporation reduced basal dendritic architecture, and that Epac2 knockdown in mature cortical neurons in vitro mimicked this effect. Overexpression of an Epac2 rare coding variant, found in human subjects diagnosed with autism, also impaired basal dendritic morphology. This mutation disrupted Epac2's interaction with Ras, and inhibition of Ras selectively interfered with basal dendrite maintenance. Finally, we observed that components of the Ras/Epac2/Rap pathway exhibited differential abundance in the basal versus apical dendritic compartments. These findings define a role for Epac2 in enabling crosstalk between Ras and Rap signaling in maintaining basal dendrite complexity, and exemplify how rare coding variants, in addition to their disease relevance, can provide insight into cellular mechanisms relevant for brain connectivity.Deepak P SrivastavaKevin M WoolfreyKelly A JonesCharles T AndersonKatharine R SmithTheron A RussellHyerin LeeMarina V YasvoinaDavid L WokosinP Hande OzdinlerGordon M G ShepherdPeter PenzesPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 10, Iss 6, p e1001350 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Deepak P Srivastava Kevin M Woolfrey Kelly A Jones Charles T Anderson Katharine R Smith Theron A Russell Hyerin Lee Marina V Yasvoina David L Wokosin P Hande Ozdinler Gordon M G Shepherd Peter Penzes An autism-associated variant of Epac2 reveals a role for Ras/Epac2 signaling in controlling basal dendrite maintenance in mice.
description	The architecture of dendritic arbors determines circuit connectivity, receptive fields, and computational properties of neurons, and dendritic structure is impaired in several psychiatric disorders. While apical and basal dendritic compartments of pyramidal neurons are functionally specialized and differentially regulated, little is known about mechanisms that selectively maintain basal dendrites. Here we identified a role for the Ras/Epac2 pathway in maintaining basal dendrite complexity of cortical neurons. Epac2 is a guanine nucleotide exchange factor (GEF) for the Ras-like small GTPase Rap, and it is highly enriched in the adult mouse brain. We found that in vivo Epac2 knockdown in layer 2/3 cortical neurons via in utero electroporation reduced basal dendritic architecture, and that Epac2 knockdown in mature cortical neurons in vitro mimicked this effect. Overexpression of an Epac2 rare coding variant, found in human subjects diagnosed with autism, also impaired basal dendritic morphology. This mutation disrupted Epac2's interaction with Ras, and inhibition of Ras selectively interfered with basal dendrite maintenance. Finally, we observed that components of the Ras/Epac2/Rap pathway exhibited differential abundance in the basal versus apical dendritic compartments. These findings define a role for Epac2 in enabling crosstalk between Ras and Rap signaling in maintaining basal dendrite complexity, and exemplify how rare coding variants, in addition to their disease relevance, can provide insight into cellular mechanisms relevant for brain connectivity.
format	article
author	Deepak P Srivastava Kevin M Woolfrey Kelly A Jones Charles T Anderson Katharine R Smith Theron A Russell Hyerin Lee Marina V Yasvoina David L Wokosin P Hande Ozdinler Gordon M G Shepherd Peter Penzes
author_facet	Deepak P Srivastava Kevin M Woolfrey Kelly A Jones Charles T Anderson Katharine R Smith Theron A Russell Hyerin Lee Marina V Yasvoina David L Wokosin P Hande Ozdinler Gordon M G Shepherd Peter Penzes
author_sort	Deepak P Srivastava
title	An autism-associated variant of Epac2 reveals a role for Ras/Epac2 signaling in controlling basal dendrite maintenance in mice.
title_short	An autism-associated variant of Epac2 reveals a role for Ras/Epac2 signaling in controlling basal dendrite maintenance in mice.
title_full	An autism-associated variant of Epac2 reveals a role for Ras/Epac2 signaling in controlling basal dendrite maintenance in mice.
title_fullStr	An autism-associated variant of Epac2 reveals a role for Ras/Epac2 signaling in controlling basal dendrite maintenance in mice.
title_full_unstemmed	An autism-associated variant of Epac2 reveals a role for Ras/Epac2 signaling in controlling basal dendrite maintenance in mice.
title_sort	autism-associated variant of epac2 reveals a role for ras/epac2 signaling in controlling basal dendrite maintenance in mice.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/82bebeeb8c44423d9a906dbfb32001e3
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An autism-associated variant of Epac2 reveals a role for Ras/Epac2 signaling in controlling basal dendrite maintenance in mice.

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