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Pistocchi, A, Fazio, G, Cereda, A, Ferrari, L, Bettini, LR, Messina, G, Cotelli, F, Biondi, A, Selicorni, A and Massa, V (2013) Cornelia de Lange Syndrome: NIPBL haploinsufficiency downregulates canonical Wnt pathway in zebrafish embryos and patients fibroblasts. Cell Death Dis 4:e866

Cornelia de Lange Syndrome is a severe genetic disorder characterized by malformations affecting multiple systems, with a common feature of severe mental retardation. Genetic variants within four genes (NIPBL (Nipped-B-like), SMC1A, SMC3, and HDAC8) are believed to be responsible for the majority of cases; all these genes encode proteins that are part of the 'cohesin complex'. Cohesins exhibit two temporally separated major roles in cells: one controlling the cell cycle and the other involved in regulating the gene expression. The present study focuses on the role of the zebrafish nipblb paralog during neural development, examining its expression in the central nervous system, and analyzing the consequences of nipblb loss of function. Neural development was impaired by the knockdown of nipblb in zebrafish. nipblb-loss-of-function embryos presented with increased apoptosis in the developing neural tissues, downregulation of canonical Wnt pathway genes, and subsequent decreased Cyclin D1 (Ccnd1) levels. Importantly, the same pattern of canonical WNT pathway and CCND1 downregulation was observed in NIPBL-mutated patient-specific fibroblasts. Finally, chemical activation of the pathway in nipblb-loss-of-function embryos rescued the adverse phenotype and restored the physiological levels of cell death.

PubMed PMC3824680 Online version:10.1038/cddis.2013.371

Animals; Apoptosis/drug effects; Cell Proliferation/drug effects; Cell Survival/drug effects; Central Nervous System/drug effects; Central Nervous System/embryology; Central Nervous System/metabolism; Child; De Lange Syndrome/embryology; De Lange Syndrome/genetics; De Lange Syndrome/pathology; Disease Models, Animal; Down-Regulation/genetics; Embryo, Nonmammalian/drug effects; Embryo, Nonmammalian/metabolism; Embryo, Nonmammalian/pathology; Female; Fibroblasts/drug effects; Fibroblasts/metabolism; Fibroblasts/pathology; Gene Expression Profiling; Gene Expression Regulation, Developmental/drug effects; Gene Knockdown Techniques; Haploinsufficiency/genetics; Humans; Male; Morpholinos/pharmacology; Phenotype; Proteins/metabolism; Wnt Signaling Pathway/drug effects; Wnt Signaling Pathway/genetics; Zebrafish/embryology; Zebrafish/genetics; Zebrafish Proteins/metabolism