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Identification of PTPD meA splicing variants

ABSTRACT: Leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) are evolutionarily conserved presynaptic cell-adhesion molecules that orchestrate multifarious synaptic adhesion pathways. Extensive alternative splicing of LAR-RPTP mRNAs, similar to neurexins, may produce innumerable LAR-RPTP isoforms that act as regulatory codes for determining the identify and strength of specific synapse signaling. However, no direct evidence for the hypothesis exists, apart from the role of LAR-RPTP splice variants in specifying region-specific, cell type-specific and neural circuit-specific properties in vivo. Here, using deep RNA sequencing (RNA-seq), we targeted Ptprs, Ptprd, and Ptprf mRNAs in diverse cell types across adult mouse brain areas. In addition to identifying novel alternatively spliced exons of Ptprd, we found pronounced cell-type-specific patterns of two microexons, meA and meB, in brain Ptprd mRNAs. Quantitative targeted proteomics uncovered profiles of LAR-RPTP proteoforms containing or lacking meA that are in line with RNA-seq results. Moreover, diverse neural circuits targeting the same neuronal popluations were dictated by the expression of different Ptprd variants characterized by distinct inclusion patterns of meA and/or meB. Remarkably, fear-related learning induced upregulation of Ptprd meA+ variants in hippocampal memory-activated dentate gyrus neurons. Furthermore, conditional ablation of Ptprd meA+ variants at presynaptic loci of distinct hippocampal circuits resulted in impairment of distinct modes of synaptic transmission and different cognitive tasks. Our data provide the first evidence of cell-type- and/or circuit-specific expression patterns and physiological functions of LAR-RPTP microexons that are dynamically regulated and likely to dictate diverse synaptic properties. In particular, we propose Ptprd splicing as a key mechanism that mediates activity-dependent neural circuit specification

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Jaewon Ko

PROVIDER: MSV000091879 | MassIVE | Mon May 08 05:32:00 BST 2023

REPOSITORIES: MassIVE

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Identification of PTPD meA splicing variants

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