Modeling the function of BAX and BAK in early human brain development using iPSC-derived systems

Area of Science:

• Cell Biology
• Developmental Biology
• Neuroscience

Background:

• Intrinsic apoptosis involves BCL-2 family proteins forming mitochondrial outer membrane pores.
• BAX and BAK are essential in murine embryogenesis and have non-canonical roles in human cancer cell apoptosis.
• The function of BAX and BAK in human brain development is largely unknown due to limited model systems.

Purpose of the Study:

• To investigate the roles of BAX and BAK in early human brain development using in vitro models.
• To determine the effects of BAX and BAK deletion on neural progenitor cells and cerebral organoids.

Main Methods:

• Generation of BAX/BAK double knockout human-induced pluripotent stem cells (hiPSCs).
• Differentiation of hiPSCs into neural progenitor cells (hNPCs), neural rosettes, and cerebral organoids.
• Analysis of mitochondrial morphology and cortical structure in BAX/BAK-deficient cells and organoids.

Main Results:

• BAX and BAK deficiency resulted in abnormal mitochondrial morphology in hiPSC-derived neural cells.
• Absence of BAX and BAK led to aberrant cortical structure formation in cerebral organoids.
• These findings highlight novel roles for BAX and BAK in maintaining mitochondrial homeostasis during neural development.

Conclusions:

• BAX and BAK play critical roles in human brain development.
• They are essential for maintaining homeostatic mitochondrial morphology in cortical progenitors and neurons.
• Human pluripotent stem cell-derived systems are valuable for studying apoptotic machinery in neural development.