The Critical Role of YAP/BMP/ID1 Axis on Simulated Microgravity-Induced Neural Tube Defects in Human Brain Organoids

Abstract

Integrated biochemical and biophysical signals regulate embryonic development. Correct neural tube formation is critical for the development of central nervous system. However, the role of microgravity in neurodevelopment and its underlying molecular mechanisms remain unclear. In this study, the effects of stimulated microgravity (SMG) on the development of human brain organoids are investigated. SMG impairs N-cadherin-based adherens junction formation, leading to neural tube defects associated with dysregulated self-renewal capacity and neuroepithelial disorganization in human brain organoids. Bulk gene expression analyses reveal that SMG alters Hippo and BMP signaling in brain organoids. The neuropathological deficits in SMG-treated organoids can be rescued by regulating YAP/BMP/ID1 axis. Furthermore, sing-cell RNA sequencing data show that SMG results in perturbations in the number and function of neural stem and progenitor cell subpopulations. One of these subpopulations senses SMG cues and transmits BMP signals to the subpopulation responsible for tube morphogenesis, ultimately affecting the proliferating cell population. Finally, SMG intervention leads to persistent neurologic damage even after returning to normal gravity conditions. Collectively, this study reveals molecular and cellular abnormalities associated with SMG during human brain development, providing opportunities for countermeasures to maintain normal neurodevelopment in space.