SynGAP splice variants display heterogeneous spatio-temporal expression and subcellular distribution in the developing mammalian brain
Gou Alsina, Gemma (Institut d'Investigació Biomèdica Sant Pau)
Roca-Fernandez, Adriana (University of Oxford)
Kilinc, Murat (The Scripps Research Institute)
Serrano, Elena (Institut d'Investigació Biomèdica Sant Pau)
Reig-Viader, R (Institut d'Investigació Biomèdica Sant Pau)
Araki, Yoichi (Johns Hopkins University)
Huganir, Richard L. (Johns Hopkins University)
de Quintana-Schmidt, Cristian (Institut d'Investigació Biomèdica Sant Pau)
Rumbaugh, Gavin (The Scripps Research Institute)
Bayés, Àlex (Institut d'Investigació Biomèdica Sant Pau)
Universitat Autònoma de Barcelona

Data:	2020
Resum:	The SynGAP protein is a major regulator of synapse biology and neural circuit function. Genetic variants linked to epilepsy and intellectual disability disrupt synaptic function and neural excitability. SynGAP has been involved in multiple signaling pathways and can regulate small GTPases with very different roles. Yet, the molecular bases behind this pleiotropy are poorly understood. We hypothesize that different SynGAP isoforms will mediate different sets of functions and that deciphering their spatio-temporal expression and subcellular localization will accelerate understanding their multiple functions. Using isoform-specific antibodies recognizing SynGAP in mouse and human samples we found distinctive developmental expression patterns for all SynGAP isoforms in five mouse brain areas. Particularly noticeable was the delayed expression of SynGAP-α1 isoforms, which directly bind to postsynaptic density-95, in cortex and hippocampus during the first 2 weeks of postnatal development. Suggesting that during this period other isoforms would have a more prominent role. Furthermore, we observed subcellular localization differences between isoforms, particularly throughout postnatal development. Consistent with previous reports, SynGAP was enriched in the postsynaptic density in the mature forebrain. However, SynGAP was predominantly found in non-synaptic locations in a period of early postnatal development highly sensitive to SynGAP levels. While, α1 isoforms were always found enriched in the postsynaptic density, α2 isoforms changed from a non-synaptic to a mostly postsynaptic density localization with age and β isoforms were always found enriched in non-synaptic locations. The differential expression and subcellular distribution of SynGAP isoforms may contribute to isoform-specific regulation of small GTPases, explaining SynGAP pleiotropy. Syngap1 gene encodes for different synaptic Ras/Rap GTPase-activating (SynGAP) isoforms which are key for brain function. SynGAP C-termini splice variants show different spatio-temporal expression and subcellular localization in the developing mouse brain. This study reveals a non-synaptic and heterogenous role of SynGAP spliced variants. Depicted abundance differences only allow relative comparison within a given tissue (top panel), postnatal age (PND, middle panel), or subcellular distribution (bottom panel). Ctx, cortex; Hip, hippocampus; Str, striatum; OB, Olfactory Bulb; Crb, cerebellum and tSynGAP, total SynGAP.
Ajuts:	Agència de Gestió d'Ajuts Universitaris i de Recerca SGR14-297 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-1776 Ministerio de Economía y Competitividad BFU2012-34398 Ministerio de Economía y Competitividad BFU2015-69717-P Ministerio de Economía y Competitividad RTI2018-097037-B-100
Nota:	Altres ajuts: Financial support for this work was provided by: Career Integration Grant (ref. 304111), Ramón y Cajal Fellowship (RYC-2011-08391p) IEDI-2017-00822; ; BES-2013-063720 (MINECO) to GG; MH096847 (NIH), MH108408 (NIH) and NS064079 (NIH) to GR and RO1 MH112151 (NIH) to RLH. All experiments were conducted in compliance with the ARRIVE guidelines.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Pleiotropy ; Postnatal development ; Protein expression pattern ; Protein isoforms ; Subcellular localization ; SynGAP
Publicat a:	Journal of Neurochemistry, Vol. 154 (march 2020) , p. 618-634, ISSN 1471-4159

DOI: 10.1111/jnc.14988
PMID: 32068252

17 p, 2.1 MB

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