PhD defence K.N. (Kristel) Eigenhuis

Below is a brief summary of the dissertation: 

The cortex occupies the largest part of the brain and enables us to experience consciousness, perform various cognitive functions, develop a personality and thus give meaning to our lives as humans. The development of the human cerebral cortex involves many genes, proteins and cell types, which are orchestrated by a tight regulation of a large number of genes.

This thesis focuses on Cornelia de Lange Syndrome (CdLS); a rare but severe neurodevelopmental disorder in which children are born with neurological abnormalities, cognitive impairments and structural malformations in the brain. CdLS is caused by a small variation in the NIPBL gene. The exact mechanisms and precise pathways that are disrupted by altered gene expression and how this leads to disrupted neurodevelopmental processes and observable changes in brain function and structure, have however remained largely elusive.

In this PhD research we generate human neuronal cell types and cortical brain organoids as a model system for brain development. The 2D and 3D neuronal model systems are generated from human stem cells in which the abnormalities in the NIPBL gene are mimicked. This allows us to investigate the consequences of a small gene variation on developmental processes that are regulated by the NIPBL gene and via which routes the disturbances in these processes lead to the manifestations of the disease in brain abnormalities and neurological symptoms.

A deeper understanding of these mechanisms and the molecular targets involved offer potential
opportunities for drug-mediated therapeutic intervention in CdLS and other neurodevelopmental disorders.