ArticleDisease models & mechanisms2023
Overexpression screen of chromosome 21 genes reveals modulators of Sonic hedgehog signaling relevant to Down syndrome.
Article in Disease models & mechanisms, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 14 citations in OpenAlex.
- A Researcher's guide to rodent models of Down syndrome: Recent insights and translational perspectives.STAR protocols · 2026Review
- Selective chr21 homolog silencing reveals polymorphisms influence the epigenetic silencing and functional dosage of RWDD2B.American journal of human genetics · 2026Article
- Trisomy 21 alters ciliary localization of Sonic Hedgehog signaling proteins.bioRxiv : the preprint server for biology · 2026Article
- Selective chr21 homolog silencing reveals polymorphisms influence the epigenetic silencing and functional dosage of RWDD2B.bioRxiv : the preprint server for biology · 2025Article
- Article
- Characterisation of aEndocrine oncology (Bristol, England) · 2025Article
- Integrated analysis of immunometabolic interactions in Down syndrome.Science advances · 2024Article
- Network Pharmacology Identifies Intersection Genes of Apigenin and Naringenin in Down Syndrome as Potential Therapeutic Targets.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Patterns of Aneuploidy and Signaling Consequences in Cancer.Cancer research · 2024Review
- Increased endothelial sclerostin caused by elevated DSCAM mediates multiple trisomy 21 phenotypes.The Journal of clinical investigation · 2024Article
- Comparative analysis of craniofacial shape in two mouse models of Down syndrome: Ts65Dn and TcMAC21.Journal of anatomy · 2024Article
- Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome.Biological research · 2023Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
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Abstract
Trisomy 21 and mutations in the Sonic hedgehog (SHH) signaling pathway cause overlapping and pleiotropic phenotypes including cerebellar hypoplasia, craniofacial abnormalities, congenital heart defects and Hirschsprung disease. 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.
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