2026-04-17T01:29:14Zhttps://recercat.cat/oai/request

oai:recercat.cat:10230/421962025-12-12T03:30:45Zcom_2072_6col_2072_452952

00925njm 22002777a 4500 dc Torres Méndez, Antonio author Bonnal, Sophie author Marquez, Yamile author Roth, Jonathan author Iglesias, Marta author Permanyer, Jon author Almudi, Isabel author O'Hanlon, Dave author Guitart, Tanit author Soller, Matthias author Gingras, Anne-Claude author Gebauer, Fátima author Rentzsch, Fabian author Blencowe, Benjamin J. author Valcárcel, J. (Juan) author Irimia Martínez, Manuel author 2019-07-29T06:13:39Z 2019 The mechanisms by which entire programmes of gene regulation emerged during evolution are poorly understood. Neuronal microexons represent the most conserved class of alternative splicing in vertebrates, and are critical for proper brain development and function. Here, we discover neural microexon programmes in non-vertebrate species and trace their origin to bilaterian ancestors through the emergence of a previously uncharacterized 'enhancer of microexons' (eMIC) protein domain. The eMIC domain originated as an alternative, neural-enriched splice isoform of the pan-eukaryotic Srrm2/SRm300 splicing factor gene, and subsequently became fixed in the vertebrate and neuronal-specific splicing regulator Srrm4/nSR100 and its paralogue Srrm3. Remarkably, the eMIC domain is necessary and sufficient for microexon splicing, and functions by interacting with the earliest components required for exon recognition. The emergence of a novel domain with restricted expression in the nervous system thus resulted in the evolution of splicing programmes that qualitatively expanded the neuronal molecular complexity in bilaterians. This work has been funded by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (ERC-StG-LS2-637591 to M.Ir. and ERC-AdvG-670146 to J.V.), the Spanish Ministry of Economy and Competitiveness (BFU2014-55076-P and BFU2017-89201-P to M.Ir., BFU2014-005153 to J.V., and the ‘Centro de Excelencia Severo Ochoa 2013–2017’ (SEV-2012-0208)), AGAUR, Fundación Botín (to J.V.) and the Canadian Institutes of Health Research (to B.J.B. and A.-C.G.). RNP mass spectrometric analyses were performed at the CRG/UPF Proteomics Unit (part of ProteoRed-PRB3, supported by PE I+D+i 2013–2016 (PT17/0019) of the ISCIII and ERDF) by ‘Programa CERCA Generalitat de Catalunya’ and ‘Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement’ (2017SGR595). A.T.-M. held an FPI-SO fellowship, and Y.M. a Marie Skłodowska-Curie individual fellowship. Comparative genomics Computational biology and bioinformatics Evolution Evolutionary developmental biology Evolutionary genetics A novel protein domain in an ancestral splicing factor drove the evolution of neural microexons