Cornelia de Lange Syndrome: different models and strategies to study the disease

Cornelia de Lange Syndrome (CdLS) is a multi-organ developmental disorder with relatively mild to severe effects. Among others, intellectual disability represents an important feature of this condition. Cornelia de Lange syndrome can result from mutations in at least five genes: NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Mutations in these genes cause CdLS by impairing the function of the cohesin complex, probably disrupting gene regulation during critical stages of early development. The cohesin complex regulates the structure and organization of chromosomes, and repair damaged DNA. In the past years, our laboratory has studied the pathogenetic mechanisms underlying CdLS exploiting several model systems. For example, murine CdLS Neural Stem Cells have been tested by inhibiting HDAC8 using PCI34051, a chemical compound known to specifically act on HDAC8 deacetylase activity, and siRNA strategies in both proliferating and differentiating cells. Moreover, canonical WNT pathway and CCND1 downregulation was observed in NIPBL- and SMC1A- mutated patient-specific fibroblasts. Drosophila melanogaster strains mutated in Nipped-B and Hdac3 genes (respectively NIPBL and HDAC8 in humans) have been used for assessing the existing correlation between cohesin complex and WNT pathway. Mutants have also been screened for chemicals (i.e. WNT activators) for reverting the CdLS associated-phenotypes as it was shown in D. rerio (zebrafish). Indeed, zebrafish models of nipbl, smc1a and hdac8 deficiency have been obtained by morpholino antisense injections. Neural development was impaired by the knockdown of these genes but chemical activation of the WNT pathway in loss-of-function embryos rescued the adverse phenotypes and restored the physiological levels of cell death.