Modeling the function of BAX and BAK in early human brain development using iPSC-derived systems
Year: 2020
Type: article
Abstract: Intrinsic apoptosis relies on the ability of the BCL-2 family to induce the formation of pores on the outer mitochondrial membrane. Previous studies have shown that both BAX and BAK are essential during murine embryogenesis, and reports in human cancer cell lines identified non-canonical roles for BAX and BAK in mitochondrial fission during apoptosis. BAX and BAK function in human brain development remains elusive due to the lack of appropriate model systems. Here, we generated BAX/BAK double knockout human-induced pluripotent stem cells (hiPSCs), hiPSC-derived neural progenitor cells (hNPCs), neural rosettes, and cerebral organoids to uncover the effects of BAX and BAK deletion in an in vitro model of early human brain development. We found that BAX and BAK-deficient cells have abnormal mitochondrial morphology and give rise to aberrant cortical structures. We suggest crucial functions for BAX and BAK during human development, including maintenance of homeostatic mitochondrial morphology, which is crucial for proper development of progenitors and neurons of the cortex. Human pluripotent stem cell-derived systems can be useful platforms to reveal novel functions of the apoptotic machinery in neural development.
Source: Cell Death and Disease
Institution: Vanderbilt University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,990
Funders: Foundation for the National Institutes of Health, American Heart Association, Vanderbilt University, National Institutes of Health, Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Environmental Health Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: (PQ5) Assessing the contribution of mitochondrial heterogeneity to gliomagenesis using single cell approaches, G2268269956, Acquisition of a super-resolution optical microscope, Non-apoptotic function of MCL-1 in regulating mitochondrial dynamics and metabolism in iPSC-derived cardiomyocytes, G3433274139, G4632492085, G4658226559, LSM880-Airyscan Confocal Microscope for Large Shared Resource, Overall: Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Center at Vanderbilt, G5853943267, G5875653355, G5992848320, G7520984233, Molecular and Cellular Basis for Digestive Diseases, Cancer Center Support Grant, Molecular Principles Governing Mitochondrial and Peroxisomal Remodeling as Drivers of Cell Fate and Identity, Training Program in Environmental Toxicology
OpenAlex ID: W3088399284