Cornelia de Lange Syndrome: NIPBL haploinsufficiency downregulates canonical Wnt pathway in zebrafish embryos and patients fibroblasts

Cornelia de Lange Syndrome (CdLS) 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, SMC1A, SMC3, HDAC8) are believed to be responsible for the majority of cases; all these genes encode proteins 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 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-offunction. Neural development was impaired by the knock-down 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 patients-specific fibroblasts. Finally, chemical activation of the pathway in nipblb-loss-of-function-embryos rescued the adverse phenotype and restored physiological levels of cell death.