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To provide novel insights into genotype\u2013phenotype correlations, we used standardized behavioural tests, magnetic resonance imaging and hippocampal gene expression to screen several DS mouse models for the mouse chromosome 16 region homologous to Hsa21. First, we unravelled several genetic interactions between different regions of chromosome 16 and how they contribute significantly to altering the outcome of the phenotypes in brain cognition, function and structure. Then, in-depth analysis of misregulated expressed genes involved in synaptic dysfunction highlighted six biological cascades centred around DYRK1A, GSK3\u03b2, NPY, SNARE, RHOA and NPAS4. Finally, we provide a novel vision of the existing altered gene\u2013gene crosstalk and molecular mechanisms targeting specific hubs in DS models that should become central to better understanding of DS and improving the development of therapies.<\/jats:p>","DOI":"10.1093\/hmg\/ddab012","type":"journal-article","created":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T08:20:09Z","timestamp":1611130809000},"page":"771-788","source":"Crossref","is-referenced-by-count":41,"title":["Multi-influential genetic interactions alter behaviour and cognition through six main biological cascades in Down syndrome mouse models"],"prefix":"10.1093","volume":"30","author":[{"given":"Arnaud","family":"Duchon","sequence":"first","affiliation":[{"name":"Universit\u00e9 de Strasbourg, CNRS, INSERM, Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire (IGBMC), department of translational medicine and neurogenetics 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"del Mar Muniz Moreno","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Strasbourg, CNRS, INSERM, Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire (IGBMC), department of translational medicine and neurogenetics 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Martin Lorenzo","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Strasbourg, CNRS, INSERM, Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire (IGBMC), department of translational medicine and neurogenetics 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcia Priscilla","family":"Silva de Souza","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Strasbourg, CNRS, INSERM, Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire (IGBMC), department of translational medicine and neurogenetics 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Chevalier","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Strasbourg, CNRS, INSERM, Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire (IGBMC), department of translational medicine and neurogenetics 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9rie","family":"Nalesso","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Strasbourg, CNRS, INSERM, Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire (IGBMC), department of translational medicine and neurogenetics 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamid","family":"Meziane","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Strasbourg, CNRS, INSERM, Institut Clinique de la Souris (ICS), CELPHEDIA, PHENOMIN, 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulo","family":"Loureiro de Sousa","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Strasbourg, CNRS UMR 7357, ICube, FMTS, 67000 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Noblet","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Strasbourg, CNRS UMR 7357, ICube, FMTS, 67000 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Paul","family":"Armspach","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Strasbourg, CNRS UMR 7357, ICube, FMTS, 67000 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronique","family":"Brault","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Strasbourg, CNRS, INSERM, Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire (IGBMC), department of translational medicine and neurogenetics 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yann","family":"Herault","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Strasbourg, CNRS, INSERM, Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire (IGBMC), department of translational medicine and neurogenetics 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France"},{"name":"Universit\u00e9 de Strasbourg, CNRS, INSERM, Institut Clinique de la Souris (ICS), CELPHEDIA, PHENOMIN, 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,3,9]]},"reference":[{"key":"2021052810103717900_ref1","first-page":"256","article-title":"Mongolism; a chromosomal disease (trisomy)","volume":"143","author":"Lejeune","year":"1959","journal-title":"Bull. 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