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

人类大脑皮层的发育是一个复杂且受到严格调控的过程。在皮质发育过程中，不同类型的细胞增殖、分化、迁移和整合，形成高度复杂的结构，为高等灵长类动物的感官知觉、认知功能和心智能力提供了结构基础。任何上述细胞过程的中断都会导致皮质发育（MCD）畸形，这是神经发育迟缓或残疾的常见原因。遗传工具和测序技术的最新进展扩大了我们对神经发育障碍（如小头畸形）遗传原因的理解。尽管如此，MCD的潜在机制仍然知之甚少。通过筛选一组患有各种脑畸形的患者，我们确定了在编码EXOSC 10的基因中携带从头突变的小头症个体，EXOSC 10是RNA衰变外泌体复合物的核心亚基。通过将基因组编辑技术与基因组方法相结合，我们在此提出：（1）产生EXOSC 10小鼠突变体并表征其皮质表型;（2）研究控制皮质发育的EXOSC 10依赖性机制;（3）阐明鉴定的从头突变如何影响EXOSC 10在皮质发育过程中的功能并最终导致小头畸形。这项研究将为EXOSC 10介导的控制小鼠和人类皮质发育的机制提供有价值的见解。

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.