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Cornelia de Lange Syndrome (CdLS), mostly caused by heterozygous mutations of Nipbl, is an autosomal dominant disease characterized by multiorgan malformations. However, the regulatory role and underlying mechanism of Nipbl in skeletal development remain largely elusive. In this study, we constructed a Nipbl\u2010a Cas9\u2010knockout (KO) zebrafish, which displayed severe retardation of global growth and skeletal development. Deficiency of Nipbl remarkably compromised cell growth and survival, and osteogenic differentiation of mammalian osteoblast precursors. Furthermore, Nipbl depletion impaired the cell cycle process, and caused DNA damage accumulation and cellular senescence. In addition, nucleolar fibrillarin expression, global rRNA biogenesis, and protein translation were defective in the Nipbl\u2010depleted osteoblast precursors. Interestingly, an integrated stress response\u00a0inhibitor (ISRIB), partially rescued Nipbl depletion\u2010induced cellular defects in proliferation and apoptosis, osteogenesis, and nucleolar function. Simultaneously, we performed transcriptome analysis of Nipbl deficiency on human neural crest cells and mouse embryonic fibroblasts in combination with\u00a0Nipbl ChIP\u2010Seq. We found that Nipbl deficiency caused thousands of differentially expressed genes including some important genes in bone and cartilage development. In conclusion, Nipbl deficiency compromised skeleton development through impairing osteoblast precursor cell proliferation and survival, and osteogenic differentiation, and also disturbing the expression of some osteogenesis\u2010regulatory genes. Our study elucidated that Nipbl played a pivotal role in skeleton development, and supported the fact that treatment of ISRIB may provide an early intervention strategy to alleviate the bone dysplasia of CdLS.<\/jats:p>","DOI":"10.1002\/jcp.30491","type":"journal-article","created":{"date-parts":[[2021,6,25]],"date-time":"2021-06-25T10:10:25Z","timestamp":1624615825000},"page":"8208-8225","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Defects of cohesin loader lead to bone dysplasia associated with transcriptional disturbance"],"prefix":"10.1002","volume":"236","author":[{"given":"Weihuai","family":"Gu","sequence":"first","affiliation":[{"name":"Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Institute of Stomatological Research Sun Yat\u2010sen University Guangzhou Guangdong 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