Molecular mechanisms causing primary microcephaly in human and mouse: case study of EXOSC10 mutations

• Applicant: Tran Cong Tuoc, Ph.D.
• Subject Area: Developmental Neurobiology ; Human Genetics
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 452515688

The development of the human cortex is a complex and tightly regulated process. During cortical development, distinct cell types proliferate, differentiate, migrate, and integrate to form a highly complex structure that provides the structural basis for the sensory perception, cognitive function, and mental ability of higher primates. Disruptions in any of the abovementioned cellular processes lead to malformations in cortical development (MCD), which are common causes of neurodevelopmental delay or disability. Recent advances in genetic tools and sequencing technologies have expanded our understanding of the genetic causes of neurodevelopmental disorders, such as microcephaly. Nonetheless, the mechanisms underlying MCD are still poorly understood. By screening a panel of patients with a wide range of brain malformations, we identified microcephalic individuals harboring de novo mutations in the genes encoding EXOSC10, which is a core subunit of the RNA-decay exosome complex. By combining a genome-editing technique with genomic approaches, we herein propose to: (1) generate EXOSC10 mouse mutants and characterize their cortical phenotypes; (2) study the EXOSC10-dependent mechanism that controls cortical development; and (3) elucidate how the identified de novo mutations influence the functions of EXOSC10 during corticogenesis and ultimately cause microcephaly. This study should provide valuable insights into the EXOSC10-mediated mechanisms that control cortical development in mouse and human.

• DFG Programme: Research Grants