Single Cell Analysis in trisomic tissues and organoids. Single Cell Analysis in trisomic tissues and organoids

DS is the most common genetic intellectual disability, and is caused by trisomy of chromosome 21 (HSA21) This should theoretically result in a 1.5 fold overexpression of all HSA21 genes. However, transcriptomic studies revealed that, probably due to the action of transcription factors and epigenetic mechanisms, the gene deregulation affected all chromosomes and not all HSA21 genes showed the expected 1.5 deregulation. Such broad transcriptional deregulation may alter the development of the cerebral cortex, a brain region involved in high-order cognitive function, and assembled from a diverse repertoire of neuronal subtypes generated during development. We still do not know how gene expression deregulation affects neuron subtypes disturbing their morphology, dendritic structure, and other characteristics in DS. In fact, bulk methods obscure cell-type diversity and provide coarse insight into this question. Thus, we propose to investigate DS using single-cell resolution transcriptomic studies to generate a high resolution picture of DS cortical neurodevelopment in vivo in a DS mouse model (Ts65Dn), and in vitro 3D brain trisomic organoids. The main aim of the project is to understand whether differential gene expression (DE) in DS brains affects cell diversity and how the molecular events that control the development of these diverse types of neocortical neurons are affected by the trisomy. We propose to compare a trisomic mouse model to wild type littermates using both forebrain fetal tissue and organoids.