Cornelia de Lange syndrome (CdLS) is a multisystem organ developmental disorder characterized by growth and cognitive deficits and premature aging, caused by mutations in genes coding for the cohesin complex. CdLS cells presented with gene expression dysregulation, genomic instability, decreased energy production and oxidative stress. Variants in the cohesin loading factor Nipped-B-like (NIPBL) gene can be identified in approximately 70% of cases and the severity of clinical presentation is closely correlated with the Nipbl expression levels determined by droplet digital PCR. In addition to the canonical role as cohesion loader, Nipbl is implicated in the regulation of gene expression, double strand DNA break repair and maintaining genomic stability. However, function of Nipbl in this syndrome is still unclear. To explore the role of Nipbl in postnatal brain development and function and the underlying mechanisms, we knocked out NIPBL postnatally in glutamatergic forebrain neurons using Cre recombinase driven by the Ca2+/Calmodulin-dependent protein kinase II alpha gene promoter (Camk2a-Cre). Specific deletion of nipbl in the brain was validated by PCR. NIPBL cKO mice exhibited growth retardation and premature death compared to their heterozygous or NIPBL floxed littermates. Brain weight was significantly reduced in the NIPBL cKO knockout pups compared to that of the control mice. However, the brain weight to body weight ratio was significantly increased in the NIPBL cKO mice, suggesting that the reduction in brain weight is secondary to overall growth retardation. Although in open field testing no alteration in mobility or anxiety-like behavior for NIPBL cKO mice, significantly higher proportion of hind limb reflex was noted, which suggested impaired brain function. Histological analysis revealed mild cell disorganization in CA region of hippocampus without obvious abnormalities in the cortex of NIPBL cKO. Furthermore, TUNEL-positive cells were significantly increased in Nipbl-deficient brains. Immunostaining showed no significantly different GFAP expression in cortex and hippocampus between genotypes. In terms of gene expression, hundreds of mRNAs and non-coding RNAs were expressed at significantly different levels between Nipbl-deficient and control hippocampus. Further, a gene ontology analysis after RNA-sequencing suggested the downregulation of genes related to metabolic processes in the NIPBL cKO mice. Our results indicate that Nipbl regulate functional neural development, possibly by regulating gene expression. These findings may provide new insight to the management in CdLS.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology