Pathomechanisms of DONSON microcephaly

• Applicant: Professor Dr. Ralf Stumm
• Subject Area: Developmental Neurobiology ; Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 538215501

Primary microcephaly is a genetically heterogeneous hereditary disorder based on impaired brain development without severe abnormalities of brain architecture. It is characterized by a reduced head circumference at birth and is associated with variable intellectual deficits. Genes affected in microcephaly are involved in various cell division processes and show partial or complete loss of function. The cerebral cortex is particularly affected because it constitutes the largest part of the brain and cortical neural stem and progenitor cells (NPCs) need to proliferate with high efficiency. Microcephaly is often explained by increased apoptosis of NPCs. Recently, it was found that the DONSON protein is a component of the replisome and is involved in the initiation of DNA replication and stabilization of the replication fork. Its partial loss of function, caused by mutations in the DONSON gene, causes microcephaly. The function of DONSON has not been studied in NPCs. Similarly, pathomechanisms triggered in NPCs by its partial or complete loss of function are unexplored. This project uses genetic mouse models that allow deletion of the Donson gene in NPCs and mimic a DONSON gene defect discovered in two microcephaly cases in Jena, Germany. It investigates pathomechanisms of microcephaly and explores intervention strategies. Preliminary work points to a new pathomechanism of microcephaly. This is triggered by partial, but not complete loss of DONSON function. We hypothesize that DNA damage in a few NPCs leads to p53-dependent activation of the Notch1 pathway in numerous NPCs. This increases symmetric division of NPCs and reduces neuronal output. The project elucidates pathomechanisms of DONSON microcephaly and advances understanding of how cortical NPCs respond to impaired DNA replication.

• DFG Programme: Research Grants