title: An autism-associated variant of Epac2 reveals a role for Ras/Epac2 signaling in controlling basal dendrite maintenance in mice.
abstract: 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.
authors: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors: Deepak P
authors: DP
authors: Srivastava
authors: Kevin M
authors: KM
authors: Woolfrey
authors: Kelly A
authors: KA
authors: Jones
authors: Charles T
authors: CT
authors: Anderson
authors: Katharine R
authors: KR
authors: Smith
authors: Theron A
authors: TA
authors: Russell
authors: Hyerin
authors: H
authors: Lee
authors: Marina V
authors: MV
authors: Yasvoina
authors: David L
authors: DL
authors: Wokosin
authors: P Hande
authors: PH
authors: Ozdinler
authors: Gordon M G
authors: GM
authors: Shepherd
authors: Peter
authors: P
authors: Penzes
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000378:metabolism; D002450:Cell Communication; D003712:Dendrites / Q000378:metabolism*; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D018631:ras Proteins
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C486707:Rapgef4 protein, mouse; D018631:ras Proteins