The cerebral cortex drives human cognition through the coordinated activity of discrete cortical areas, each harboring specialized molecular, structural and functional characteristics. Central to this organization is the prefrontal cortex (PFC), a hub for executive function that displays disproportionate expansion in humans and selective vulnerability to neurodevelopmental disorders. Previous work has identified a collection of PFC-enriched marker genes with dynamic expression trajectories, and re-analysis of these datasets converge these markers into 18 distinct molecular signatures of spatiotemporal PFC identity. However, the intrinsic gene networks that coordinate these molecular signatures to shape the human PFC remains unclear. Through pooled CRISPR activation screens in human primary cortical tissues, we have evaluated the ability of PFC-enriched transcription factors to intrinsically pattern PFC molecular identity. Our screens identify novel roles for the neurogenesis regulator, YBX1, in the activation of human PFC fate. In parallel screens and knock-down experiments in human cortical organoids, we define how YBX1 acts in concert with other PFC determinants to activate molecular signatures of PFC identity. Our findings support a model in which PFC patterning is orchestrated by cohorts of intrinsic determinants that initiate, potentiate, and modulate PFC gene signatures, conferring robustness to the development of the human PFC. ### Competing Interest Statement The authors have declared no competing interest. NIH, R00NS111731, R01MH132689, UM1MH130991, RF1MH132662, U24HG002371 Brain & Behavior Research Foundation, https://ror.org/03a63f080, Young Investigator Award Alfred P. Sloan Foundation, https://ror.org/052csg198, Sloan Fellowship Rose Hills Foundation, Innovation Award Esther A. & Joseph Klingenstein Fund, Klingenstein-Simons Fellowship Simons Foundation, https://ror.org/01cmst727, Klingenstein-Simons Fellowship Ablon Trust, Ablon Scholar Award Department of Biological Chemistry, UCLA Zamenhof Scholarship UCLA Eli and Edythe Broad Center of Regenerative Medicine, Innovation Award, Stem Cell Research Training Program University of California, Los Angeles, https://ror.org/046rm7j60, Eugene V. Cota-Robles Award California Institute for Regenerative Medicine, https://ror.org/033m8b439, DISC0-14514, DISC4-16337 National Science Foundation, Graduate Research Fellowship Program

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