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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,8,2]]},"abstract":"<jats:p>\n                    Ribosomal RNA (rRNA) transcription by RNA polymerase I (Pol I) is a critical rate-limiting step in ribosome biogenesis, which is essential for cell survival. Despite its global function, disruptions in ribosome biogenesis cause tissue-specific birth defects called ribosomopathies, which frequently affect craniofacial development. Here, we describe a cellular and molecular mechanism underlying the susceptibility of craniofacial development to disruptions in Pol I transcription. We show that Pol I subunits are highly expressed in the neuroepithelium and neural crest cells (NCCs), which generate most of the craniofacial skeleton. High expression of Pol I subunits sustains elevated rRNA transcription in NCC progenitors, which supports their high tissue-specific levels of protein translation, but also makes NCCs particularly sensitive to rRNA synthesis defects. Consistent with this model, NCC-specific deletion of Pol I subunits\n                    <jats:italic>Polr1a<\/jats:italic>\n                    ,\n                    <jats:italic>Polr1c<\/jats:italic>\n                    , and associated factor\n                    <jats:italic>Tcof1<\/jats:italic>\n                    in mice cell-autonomously diminishes rRNA synthesis, which leads to p53 protein accumulation, resulting in NCC apoptosis and craniofacial anomalies. Furthermore, compound mutations in Pol I subunits and associated factors specifically exacerbate the craniofacial anomalies characteristic of the ribosomopathies Treacher Collins syndrome and Acrofacial Dysostosis\u2013Cincinnati type. Mechanistically, we demonstrate that diminished rRNA synthesis causes an imbalance between rRNA and ribosomal proteins. This leads to increased binding of ribosomal proteins Rpl5 and Rpl11 to Mdm2 and concomitantly diminished binding between Mdm2 and p53. Altogether, our results demonstrate a dynamic spatiotemporal requirement for rRNA transcription during mammalian cranial NCC development and corresponding tissue-specific threshold sensitivities to disruptions in rRNA transcription in the pathogenesis of congenital craniofacial disorders.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2116974119","type":"journal-article","created":{"date-parts":[[2022,7,26]],"date-time":"2022-07-26T14:37:08Z","timestamp":1658846228000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":70,"title":["Dynamic regulation and requirement for ribosomal RNA transcription during mammalian development"],"prefix":"10.1073","volume":"119","author":[{"given":"Karla T.","family":"Falcon","sequence":"first","affiliation":[{"name":"Stowers Institute for Medical Research, Kansas City, MO 64110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3933-6946","authenticated-orcid":false,"given":"Kristin E. 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