title: Cornelia de Lange Syndrome: NIPBL haploinsufficiency downregulates canonical Wnt pathway in zebrafish embryos and patients fibroblasts.
abstract: 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.
authors.affiliation: 1] Department of Medical Biotechnologies and Translational Medicine, University of Milan, Via Viotti, 3/5, 20133, Milan, Italy [2] Department of Biosciences, University of Milan, Via Celoria, 26, 20133, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Pistocchi
authors.forename: G
authors.initials: G
authors.lastname: Fazio
authors.forename: A
authors.initials: A
authors.lastname: Cereda
authors.forename: L
authors.initials: L
authors.lastname: Ferrari
authors.forename: L R
authors.initials: LR
authors.lastname: Bettini
authors.forename: G
authors.initials: G
authors.lastname: Messina
authors.forename: F
authors.initials: F
authors.lastname: Cotelli
authors.forename: A
authors.initials: A
authors.lastname: Biondi
authors.forename: A
authors.initials: A
authors.lastname: Selicorni
authors.forename: V
authors.initials: V
authors.lastname: Massa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D002648:Child; D003635:De Lange Syndrome / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D055785:Gene Knockdown Techniques; D057895:Haploinsufficiency / Q000235:genetics*; D006801:Humans; D008297:Male; D060172:Morpholinos / Q000494:pharmacology; D010641:Phenotype; D011506:Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics*; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000378:metabolism*; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D060172:Morpholinos; D011506:Proteins; D029961:Zebrafish Proteins; C487465:NIPBL protein, human; C570219:nipblb protein, zebrafish; D000097722:Cohesins