Decoding neural precursors' role in shaping the convoluted fetal cortex

About This Grant

ABSTRACT. Fetal development remains one of the final frontiers in medical science. It is an exceptionally brief period during which rapid, precise biological processes must unfold to ensure a successful transition to life outside the womb and normal function after birth. In the fetal period, human neural precursors generate a vast number of neurons and glia in a highly regulated manner to form the intricate, gyrencephalic brain providing the extraordinary computational power. The pre- and perinatal periods are recognized as critical windows for our neurological and behavioral development, representing both a significant risk and an opportunity for intervention. Unraveling the developmental mechanisms of the fetal brain thus has far-reaching implications, extending beyond prenatal and neurodevelopmental disorders to conditions related to aging. Despite recent advances in understanding the diversity of neural precursors and their genetic regulation, most research has been conducted in the lissencephalic mouse model. Emerging evidence from gyrencephalic species suggests that neural precursor types and their developmental mechanisms are differently tuned in species with larger, more complex brains. Notably, cortical gyrification appears to result from the coordinated actions of multiple factors interacting at different levels. Studies in mouse, ferret, macaque, and human brains have shown that key events underlying this process include region-specific neurogenesis in the ventricular and subventricular zones (VZ/SVZ) and the tangential dispersion of radial glial cells. We thus hypothesize that the spatiotemporal modulation of specific neural precursors in the VZ/SVZ plays critical role in the formation of a convoluted cortical structure. While single- cell transcriptomic data from species with complex brains, such as ferret and non-human primates, have provided insights into gene expression patterns, prenatal in vivo confirmation of these findings is challenging due to limitations in existing models. To address these challenges, we will establish a new fetal model, the Göttingen minipig, to study the prenatal mechanisms of gyrencephalic neocortical development - one of the key unresolved questions in neuroscience. Pigs provide a powerful model for studying complex brain development. The cytoarchitecture of the porcine VZ/SVZ closely mirrors that of humans, and our recent single-cell sequencing has identified unique cell populations in the piglet SVZ that are also present in humans but absent in rodents. Notably, for the first time, we have successfully established an in utero electroporation technique in fetal minipigs, allowing us to genetically label VZ/SVZ precursors with specific plasmid probes. By leveraging this unique model in combination with modern genetic and cellular imaging techniques, we will characterize germinal regions and identify and test key cellular/molecular events that contribute to the construction of a gyrencephalic neocortex. This study will provide the first direct evidence linking the modulation of specific neural precursors to structural changes in the fetal gyrencephalic neocortex. Such insights will be transformative not only for understanding cortical formation but also for improving outcomes in a wide range of neurodevelopmental disorders.