Ripply3overdosage induces mid-face shortening throughTbx1downregulation in Down syndrome models

• DOI: 10.1101/2024.09.13.612914
• Publication Date: 2024-09-16T05:40:16Z
• Authors: José Tomás Ahumad...; Claire Chevalier; Agnes Bloch Zupan; Yann Herault

ABSTRACTThe most frequent and unique features of Down syndrome (DS) are learning disability and ucraniofacial (CF) dysmorphism. The DS-specific CF features are an overall reduction in head dimensions (microcephaly), relatively wide neurocranium (brachycephaly), reduced mediolaterally orbital region, reduced bizygomatic breadth, small maxilla, small mandible, and increased individual variability. Until now, the cellular and molecular mechanisms underlying the specific craniofacial phenotype have remained poorly understood. Investigating a new panel of DS mouse models with different segmental duplications on mouse chromosome 16 in the region homologous to human chromosome 21, we identified new regions and the role of two candidate gene for DS-specific CF phenotypes. First, we confirmed the role ofDyrk1ain the neurocranium brachycephaly. Then, we identified the role of the transcription factorRipply3overdosage in midface shortening through the downregulation ofTbx1, another transcription factor involved in the CF midface phenotype encountered in DiGeorge syndrome. This last effect occurs during branchial arches development through a reduction in cell proliferation. Our findings define a new dosage-sensitive gene responsible for the DS craniofacial features and propose new models for rescuing all aspects of DS CF phenotypes. This data may also provide insights into specific brain and cardiovascular phenotypes observed in DiGeorge and DS models, opening avenues for potential targeted treatment to soften craniofacial dysmorphism in Down syndrome.