Molecular mechanisms underlying neural development impairment in CdLS models
Cornelia de Lange Syndrome (CdLS) is a rare genetic disease, affecting multiple organs including the central nervous system (CNS). CdLS is mainly caused by dominant autosomal or X-linked mutations in five genes: NIPBL, SMC1A, SMC3, RAD21, and HDAC8. These genes encode for proteins of the cohesin complex, which plays a pivotal role in gene expression regulation. Indeed, we and others have previously reported that the canonical WNT pathway, a master controller of neurodevelopment, is downregulated in CdLS models.
Here, we explored possible ameliorative effects of chemical activation of WNT pathway in in vitro and in vivo CdLS models. First, we treated lymphoblastoid cell lines from healthy donors and CdLS patients with activators of the WNT pathway during the exponential phase of growth. We have found that lithium treatment restored proliferation rate and induced CyclinD1 gene expression, which are usually found reduced in cells of CdLS patients. We then analyzed an in vitro murine model of CdLS, in which neural stem cells proliferation and differentiation are significantly reduced. Such defects were rescued upon chemical exposure to lithium. Finally, we used a Drosophila melanogaster CdLS model which shows abnormal development of the mushroom body (MB), a CNS structure involved in learning and memory. Upon feeding on lithium, a significant rescue of MB morphology was observed across generations.
Together, our data confirm impairment of WNT canonical pathway in CdLS, possibly explaining the typical neurodevelopmental alterations, and reveal that WNT activators, such as lithium, could contribute to develop CdLS therapies in the future.
Conflicts of interest: none.
Worldconference 2019, Germany and Netherlands, Ahrweiler, published on 31 jul. 2019
