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Nuclear import of the DSCAM ‐cytoplasmic domain drives signaling capable of inhibiting synapse formation
Author(s) -
Sachse Sonja M,
Lievens Sam,
Ribeiro Luís F,
Dascenco Dan,
Masschaele Delphine,
Horré Katrien,
Misbaer Anke,
Vanderroost Nele,
De Smet Anne Sophie,
Salta Evgenia,
Erfurth MariaLuise,
Kise Yoshiaki,
Nebel Siegfried,
Van Delm Wouter,
Plaisance Stéphane,
Tavernier Jan,
De Strooper Bart,
De Wit Joris,
Schmucker Dietmar
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201899669
Subject(s) - biology , microbiology and biotechnology , cytoplasm , signal transduction , immunological synapse , lim domain , domain (mathematical analysis) , synapse , immunology , genetics , neuroscience , transcription factor , gene , t cell , t cell receptor , immune system , mathematical analysis , mathematics , zinc finger
DSCAM and DSCAML 1 are immunoglobulin and cell adhesion‐type receptors serving important neurodevelopmental functions including control of axon growth, branching, neurite self‐avoidance, and neuronal cell death. The signal transduction mechanisms or effectors of DSCAM receptors, however, remain poorly characterized. We used a human ORF eome library to perform a high‐throughput screen in mammalian cells and identified novel cytoplasmic signaling effector candidates including the Down syndrome kinase Dyrk1a, STAT 3, USP 21, and SH 2D2A. Unexpectedly, we also found that the intracellular domains ( ICD s) of DSCAM and DSCAML 1 specifically and directly interact with IPO 5, a nuclear import protein of the importin beta family, via a conserved nuclear localization signal. The DSCAM ICD is released by γ‐secretase‐dependent cleavage, and both the DSCAM and DSCAML 1 ICD s efficiently translocate to the nucleus. Furthermore, RNA sequencing confirms that expression of the DSCAM as well as the DSCAML 1 ICD s alone can profoundly alter the expression of genes associated with neuronal differentiation and apoptosis, as well as synapse formation and function. Gain‐of‐function experiments using primary cortical neurons show that increasing the levels of either the DSCAM or the DSCAML 1 ICD leads to an impairment of neurite growth. Strikingly, increased expression of either full‐length DSCAM or the DSCAM ICD , but not the DSCAML 1 ICD , significantly decreases synapse numbers in primary hippocampal neurons. Taken together, we identified a novel membrane‐to‐nucleus signaling mechanism by which DSCAM receptors can alter the expression of regulators of neuronal differentiation and synapse formation and function. Considering that chromosomal duplications lead to increased DSCAM expression in trisomy 21, our findings may help uncover novel mechanisms contributing to intellectual disability in Down syndrome.