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Branch point strength controls species-specific CAMK2B alternative splicing and regulates LTP

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Item Type:Article
Title:Branch point strength controls species-specific CAMK2B alternative splicing and regulates LTP
Creators Name:Franz, A. and Weber, A.I. and Preußner, M. and Dimos, N. and Stumpf, A. and Ji, Y. and Moreno-Velasquez, L. and Voigt, A. and Schulz, F. and Neumann, A. and Kuropka, B. and Kuehn, R. and Urlaub, H. and Schmitz, D. and Wahl, M.C. and Heyd, F.
Abstract:Regulation and functionality of species-specific alternative splicing has remained enigmatic to the present date. Calcium/calmodulin-dependent protein kinase IIβ (CaMKIIβ) is expressed in several splice variants and plays a key role in learning and memory. Here, we identify and characterize several primate-specific CAMK2B splice isoforms, which show altered kinetic properties and changes in substrate specificity. Furthermore, we demonstrate that primate-specific CAMK2B alternative splicing is achieved through branch point weakening during evolution. We show that reducing branch point and splice site strengths during evolution globally renders constitutive exons alternative, thus providing novel mechanistic insight into cis-directed species-specific alternative splicing regulation. Using CRISPR/Cas9, we introduce a weaker, human branch point sequence into the mouse genome, resulting in strongly altered Camk2b splicing in the brains of mutant mice. We observe a strong impairment of long-term potentiation in CA3-CA1 synapses of mutant mice, thus connecting branch point-controlled CAMK2B alternative splicing with a fundamental function in learning and memory.
Keywords:Alternative Splicing, Base Sequence, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Exons, Long-Term Potentiation, RNA Splicing, Animals, Mice
Source:Life Science Alliance
ISSN:2575-1077
Publisher:Life Science Alliance
Volume:6
Number:3
Page Range:e202201826
Date:March 2023
Official Publication:https://doi.org/10.26508/lsa.202201826
PubMed:View item in PubMed

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