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Trisomic cells derived from individuals with Down syndrome possess deficits in SHH signaling, suggesting that overexpression of human chromosome 21 genes may contribute to SHH-associated phenotypes by disrupting normal SHH signaling during development. However, chromosome 21 does not encode any known components of the canonical SHH pathway. Here, we sought to identify chromosome 21 genes that modulate SHH signaling by overexpressing 163 chromosome 21 cDNAs in a series of SHH-responsive mouse cell lines. We confirmed overexpression of trisomic candidate genes using RNA sequencing in the cerebella of Ts65Dn and TcMAC21 mice, model systems for Down syndrome. Our findings indicate that some human chromosome 21 genes, including DYRK1A, upregulate SHH signaling, whereas others, such as HMGN1, inhibit SHH signaling. Individual overexpression of four genes (B3GALT5, ETS2, HMGN1 and MIS18A) inhibits the SHH-dependent proliferation of primary granule cell precursors. Our study prioritizes dosage-sensitive chromosome 21 genes for future mechanistic studies. Identification of the genes that modulate SHH signaling may suggest new therapeutic avenues for ameliorating Down syndrome phenotypes.<\/jats:p>","DOI":"10.1242\/dmm.049712","type":"journal-article","created":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T10:10:35Z","timestamp":1680171035000},"source":"Crossref","is-referenced-by-count":15,"title":["Overexpression screen of chromosome 21 genes reveals modulators of Sonic hedgehog signaling relevant to Down syndrome"],"prefix":"10.1242","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1912-1745","authenticated-orcid":false,"given":"Anna J.","family":"Moyer","sequence":"first","affiliation":[{"name":"Johns Hopkins University School of Medicine 1 Department of Genetic Medicine , , Baltimore, MD 21205 , USA"},{"name":"Johns Hopkins University School of Medicine 2 Department of Physiology , , Baltimore, MD 21205 , USA"},{"name":"University of Alabama at Birmingham 3 Department of Neurobiology , , Birmingham, AL 35233 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4288-5383","authenticated-orcid":false,"given":"Fabian-Xos\u00e9","family":"Fernandez","sequence":"additional","affiliation":[{"name":"University of Arizona 4 Department of Psychology , , Tucson, AZ 85724 , USA"},{"name":"University of Arizona 5 Department of Neurology , , Tucson, AZ 85724 , USA"},{"name":"BIO5 and McKnight Brain Research Institutes 6 , Tucson, AZ 85721 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yicong","family":"Li","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine 2 Department of Physiology , , Baltimore, MD 21205 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9901-3682","authenticated-orcid":false,"given":"Donna K.","family":"Klinedinst","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine 2 Department of Physiology , , Baltimore, MD 21205 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8124-2324","authenticated-orcid":false,"given":"Liliana D.","family":"Florea","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine 1 Department of Genetic Medicine , , Baltimore, MD 21205 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Kazuki","sequence":"additional","affiliation":[{"name":"School of Life Science, Faculty of Medicine and Chromosome Engineering Research Center, Tottori University 7 Division of Genome and Cellular Functions, Department of Molecular and Cellular Biology , , 86 Nishi-cho, Yonago, Tottori 683-8503 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuo","family":"Oshimura","sequence":"additional","affiliation":[{"name":"Chromosome Engineering Research Center, Tottori University 8 , Yonago, Tottori 683-8503 , Japan"},{"name":"Trans Chromosomics, Inc. 9 , 86 Nishi-cho, Yonago, Tottori 683-8503 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3581-0850","authenticated-orcid":false,"given":"Roger H.","family":"Reeves","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine 1 Department of Genetic Medicine , , Baltimore, MD 21205 , USA"},{"name":"Johns Hopkins University School of Medicine 2 Department of Physiology , , Baltimore, MD 21205 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2023,4,13]]},"reference":[{"key":"2023041307404575700_","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1002\/ajmg.a.31721","article-title":"Differential effects of trisomy on brain shape and volume in related aneuploid mouse models","volume":"143A","author":"Aldridge","year":"2007","journal-title":"Am. 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