Excellence in Research: The role of Neuregulin-1 in proliferation and differentiation of brain cortical neuronal stem cells during fetal development

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Neuregulins (NRGs) are a family of structurally related signaling proteins that bind to receptor tyrosine kinases of the ErbB family and mediate a myriad of cellular functions including survival, proliferation, and differentiation in both neuronal and non-neural systems. Signaling mediated by Neuregulin-1 (NRG-1) and its receptor ErB4 plays a critical role in brain development and functions. This project will use conglomerations of neurons grown in cell culture (called “cortical organoids”), as well as experiments in mice, to investigate the role of Neuregulin-1 and its receptor ErbB4 in brain development. Because deletion of the NGR1 gene is lethal in embryonic mice, cortical organoids are used as a substitute to elucidate its role in brain development. Parallel comparisons in mice will enable validation of observed effects and provide a new platform amenable to manipulation and hypothesis testing that was not previously possible. Furthermore, understanding the effects of NRG1 on cell proliferation and differentiation in cortical neurons will unveil key mechanisms mediating brain morphogenesis. The proposed study will advance the field by generating a developmental map of Neuregulin-1/ErbB4 expression and cellular localization. The project provides a unique opportunity for mentoring underrepresented high school, minority undergraduate and graduate students as well as postdoctoral fellows to participate in cutting edge 3D organoid tissue engineering research at Morehouse School of Medicine, that will position them to pursue STEM careers with the ultimate goal of enhancing the diversity of the scientific workforce in the USA.Neuregulins (NRGs) mediate various functions associated with the development and maintenance of the nervous system, breast, heart, and other organs. NRG-1 is of great interest because it regulates cell maintenance, differentiation, proliferation, migration, and apoptosis in neuronal and non-neuronal cell types. While the role of NRG-1 in fetal development has been reported, its role in signaling mechanisms during brain development is not well understood. The role of NRG-1/ErbB4 signaling, as well as its crosstalk with factors (biomarkers) associated with neural stem cell (NSC) proliferation and differentiation, neural migration and cellular maturation during brain cortex development remains unknown. This project examines how NRG-1 mediates normal brain cortical development via an ErbB4-dependent pathway involving moderators (effectors) of cell cycle, neural migration, differentiation, and cellular maturation. Region-specific expression and function of NRG-1 and its receptor ErbB4 in human cortical organoids (either alone or in co-culture with microglial cells) will be compared with cortices of NRG-1 deficient mice to elucidate the role of NRG-1 in brain development. Multiple techniques including Digital Space Profiling (DSP), signals of proteins secreted from single cells (IsoPlexis), biological imaging (confocal, light sheet and 2-photon microscopy), immunohistochemistry (IHC), Western blotting and single cell RNA sequencing (scRNA seq) will be used to compare cellular expression and function of NRG-1 in human and murine cortical organoid development. Crosstalk between NRG1/ErbB4 signaling and developmental factors during cortical brain development will be assessed. This project will clarify the role of NRG-1/ErbB4 signaling in the development of a functional brain.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.