Identifying human-specific neural progenitors and their role in neurodevelopment

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PROJECT SUMMARY/ABSTRACT Humans have highly advanced cognitive abilities and motor skills, characteristics which are reflected in the enlarged size and cell diversity of our central nervous system (CNS). My overall goal is to profile and compare progenitor cell diversity in humans, non-human primates and rodents, and thereby identify the origins of increased cell diversity and size of the human CNS. As part of my postdoctoral research, I collected and analyzed high-temporal-resolution single-cell RNA-seq data of the well characterized human and mouse spinal motor neuron (MN) lineage, which led to the identification of a molecularly distinct, human-specific (i.e., not found in mouse) motor neuron progenitor (hsPMN) cell type. I found that hsPMNs undergo delayed and protracted neurogenesis, increasing total MN output by ~2-fold. The proposed study aims to characterize how they contribute to the population size and subtype diversity of the MN lineage by combining single-cell RNA-seq with long-term astrocyte co-culture or xeno-transplantation of lineage-labeled human cells. Second, the proposed study will further investigate the evolution of hsPMN cells and their gene expression program by a) determining whether an orthologous cell type is found in old-world monkeys (i.e., macaque), and b) identifying and functionally testing newly evolved gene regulatory elements that give rise to hsPMN-specific gene expression patterns. Finally, I will develop a 3D spinal organoid in vitro differentiation system that harbors spatially patterned ventral and dorsal spinal lineages, using a standard set of differentiation conditions that can be applied to human, macaque, and mouse cells. This last aim will broaden the scope of comparative investigations to encompass multiple spinal lineages, thus opening up new avenues and hypotheses for future research, as well as providing a more comprehensive in vitro model system of spinal cord development. The insights, protocols, and data generated from this study will enable and provide valuable comparative analyses into human neural progenitor diversity and how human-specific progenitors contribute to the size and cell diversity of the CNS during development. Furthermore, these studies and data will form the foundation of my research agenda as an independent investigator, while allow me to broaden my research training to include a diverse host of species, model systems and a wide array of experimental as well as computational techniques.