Neurodevelopmental disorders (NDD) result in variable neurological and psychological impairments. Here, we focus on microcephaly-associated NDDs that are characterized by a critical decrease in brain size, primarily caused by impaired neural stem and progenitor cell (NPC) expansion in the fetal neocortex. Previously, gene mutations associated with abnormal cell cycle progression, centrosome formation and DNA repair have been identified, yet a large proportion of microcephaly patients do not display known mutations, indicating that our knowledge of the etiology of this disorder is incomplete. Recently, we revealed an unexpected function of a microcephaly gene, Mcph1, in NPC metabolism and its critical role in NPC expansion, suggesting that a derailed NPC metabolism may contribute to microcephaly-associated NDDs. Exploiting the complementary expertises of our consortium, we propose to investigate on a broader scale the metabolism of NPCs, which depends on the metabolic microenvironment provided by the blood circulatory system and feeds into the epigenetic regulation of NPC proliferation. Moreover, we will expand the genetic analysis of our large cohort of microcephaly patients to include metabolic and epigenetic genes and explore the causality of identified mutations. Taken together, we focus on the metabolic-epigenetic interplay to advance our knowledge of the etiology of microcephaly-associated NDDs to improve diagnostic strategies and identify potential druggable targets.
Gene targeting in the brain, Stem cells and neural differentiation/cell therapy, (epi)genetic approaches, omics approaches, Patient cohorts, Animal studies, Metabolism; Neocortical development; Epigenetics