RhoGEF9 splice isoforms influence neuronal maturation and synapse formation downstream of alpha 2 GABA(A) receptors

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http://hdl.handle.net/10138/231622

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de Groot , C , Floriou-Servou , A , Tsai , Y-C , Fruh , S , Kohler , M , Parkin , G , Schwerdel , C , Bosshard , G , Kaila , K , Fritschy , J-M & Tyagarajan , S K 2017 , ' RhoGEF9 splice isoforms influence neuronal maturation and synapse formation downstream of alpha 2 GABA(A) receptors ' , PLoS Genetics , vol. 13 , no. 10 , 1007073 . https://doi.org/10.1371/journal.pgen.1007073

Title: RhoGEF9 splice isoforms influence neuronal maturation and synapse formation downstream of alpha 2 GABA(A) receptors
Author: de Groot, Claire; Floriou-Servou, Amalia; Tsai, Yuan-Chen; Fruh, Simon; Kohler, Manuela; Parkin, Georgia; Schwerdel, Cornelia; Bosshard, Giovanna; Kaila, Kai; Fritschy, Jean-Marc; Tyagarajan, Shiva K.
Contributor: University of Helsinki, Kai Kaila / Principal Investigator
Date: 2017-10
Language: eng
Number of pages: 27
Belongs to series: PLoS Genetics
ISSN: 1553-7404
URI: http://hdl.handle.net/10138/231622
Abstract: In developing brain neuronal migration, dendrite outgrowth and dendritic spine outgrowth are controlled by Cdc42, a small GTPase of the Rho family, and its activators. Cdc42 function in promoting actin polymerization is crucial for glutamatergic synapse regulation. Here, we focus on GABAergic synapse-specific activator of Cdc42, collybistin ( CB) and examine functional differences between its splice isoforms CB1 and CB2. We report that CB1 and CB2 differentially regulate GABAergic synapse formation in vitro along proximal-distal axis and adult-born neuron maturation in vivo. The functional specialization between CB1 and CB2 isoforms arises from their differential protein half-life, in turn regulated by ubiquitin conjugation of the unique CB1 C-terminus. We report that CB1 and CB2 negatively regulate Cdc42; however, Cdc42 activation is dependent on CB interaction with gephyrin. During hippocampal adult neurogenesis CB1 regulates neuronal migration, while CB2 is essential for dendrite outgrowth. Finally, using mice lacking Gabra2 subunit, we show that CB1 function is downstream of GABA(A)Rs, and we can rescue adult neurogenesis deficit observed in Gabra2 KO. Overall, our results uncover previously unexpected role for CB isoforms downstream of alpha 2-containing GABA(A)Rs during neuron maturation in a Cdc42 dependent mechanism.
Subject: OLFACTORY-BULB
INHIBITORY SYNAPSES
GABAERGIC SYNAPSES
GRANULE CELLS
GEPHYRIN
COLLYBISTIN
KINASE
CDC42
NEUROGENESIS
REGULATOR
3112 Neurosciences
1184 Genetics, developmental biology, physiology
1182 Biochemistry, cell and molecular biology
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