# Elucidating Regulation of Cell Fate Specification in Human Cortical Development to Understand Etiology of Neurodevelopment Disorders > **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $682,470 ## Abstract PROJECT SUMMARY The human brain has an expanded cortex compared to its closest relatives, and this outer layer of the brain provides humans with complex functions including integration of sensory inputs, judgement, and conscious decision making. Each of these areas of the cortex contains unique cell types, density of cells across layers, transcriptional identities, and connectivity patterns that emerge during developmental timepoints. Importantly, virtually all neurodevelopmental and neuropsychiatric disorders develop with cortical area specific phenotypes, and often with specific laminar manifestations as well. The vulnerabilities to these disorders are established during these developmental timepoints. While the existence of early morphogenetic gradients is known to establish the poles of the cortical areas, and “inside-out” neurogenesis lays the foundations for the six layers of the cortical plate, open questions regarding the transcriptional regulators of these terminal fates remains partially unknown in the developing human brain. Recent efforts through the BRAIN Initiative and others have generated expansive single-cell characterizations of the developing human cortex, providing an opportunity to mine these datasets in order to identify novel regulators of these cell fate specification events. Additionally, previous work characterizing the developing human brain has generated an “atlas of arealization” that identifies the genes that are expressed in each cortical area across developmental time. This dataset serves as a hypothesis generating tool for the identification of specific mechanisms of cortical arealization. Cortical organoids are three-dimensional models of the developing human brain that enable genetic access to and mechanistic interrogation of the developing human brain. These models have revolutionized our ability to model and characterize human development and neurodevelopmental disease, but recent characterizations of the system have identified that these organoids are not cortical area specific, but can be used for the exploration of terminal specification factors. Understanding the detailed mechanisms of cortical arealization and laminar specification could enable not only more specific understanding of disease etiology, but could also improve organoid models for the study of normal development and disease. Thus, this proposal will evaluate the signals that drive cortical arealization and laminar identity using both a bioinformatic and CRISPR activation screen. Additional efforts will explore the timing and permanence of these specification factors via knockdown of candidate regulators; proof of the pipeline will be executed with the factors identified in our preliminary studies related to the specification of FEZF2 deep layer neurons. Together, these studies will establish mechanisms and models of arealization and laminar identity in the developing human brain. ## Key facts - **NIH application ID:** 10882403 - **Project number:** 1R01MH132689-01A1 - **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES - **Principal Investigator:** Aparna Bhaduri - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $682,470 - **Award type:** 1 - **Project period:** 2024-08-15 → 2029-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10882403 ## Citation > US National Institutes of Health, RePORTER application 10882403, Elucidating Regulation of Cell Fate Specification in Human Cortical Development to Understand Etiology of Neurodevelopment Disorders (1R01MH132689-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10882403. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*