Mechanistic dissection of Polycomb-dependent dysregulation in Weaver syndrome neural lineages

Weaver syndrome (WS) is a rare and so far, neglected disease characterized by overgrowth, facial morphology aberrations and intellectual disability. Recently it has been associated to mutations in the different components of the Polycomb complex, well-known for its role in repressing the expression. There is not much is known about its function during human brain development, mainly due to the fact that most studies have been performed in animal models with genetic lesions that do not reflect the reality of the disease in the patients. In this project we pilot a new approach that addresses these problems through the use of new highly informative models. We are harnessing the use of stem cells coming directly from patients, that are then the base from which we can recreate the affected tissues in vitro, namely, the developing brain through differentiation of neurons and their 3-dimensional version called “brain organoids”, and the generation of the cells that produce the face structure, called neural crest cells. We will then profile these tissues using advanced informatic analysis to identify the biological processes affected that end up causing the disease. With this strategy, we aim to define the molecular targets more directly linked to the development of this disease and propose mechanistic strategies that pave the way to their validation as possible therapeutic targets.