Modelling monogenic neurodevelopmental disorders: A multi-level analysis across species

Brain development is an intricate process that involves a sequence of steps tightly regulated in time and space, orchestrated by specific expression patterns in various cell types. When a single aspect of brain development is disrupted, structural and functional problems can arise, leading to neurodevelopmental disorders (NDDs). These are rare syndromes, with genetic and environmental causes, whose main symptoms include intellectual disability, autism spectrum disorders, attention-deficit/hyperactivity, schizophrenia and motor and language disorders. In this thesis, we investigated, across various disease models, the pathogenic mechanisms of two rare monogenic disorders: Witteveen-Kolk Syndrome (WITKOS) and Lesch-Nyhan Disease (LND). In WITKOS, a transcriptional regulator, SIN3A, is affected, whereas in LND, the impairment occurs at the metabolic level, as the enzyme responsible for purine recycling, HGprt, is not functional. Despite the different molecular mechanisms, both WITKOS and LND converge on a common outcome: altered brain development that underlies the cognitive and behavioural problems encountered in these two NDDs. By integrating diverse experimental systems and biological levels, we illustrate how a multi-model strategy, combining human (iPSC-derived neural organoids and assembloids), mouse and zebrafish models, can provide complementary insights into disease mechanisms, which could have a valuable impact on the study design of other NDDs and improve the design of therapeutic interventions.