Low oxygen (O2) partial pressure results in decreased ATP levels via reduction in oxidative phosphorylation – which is most acutely experienced in organs with high metabolic demand. Hence it is not surprising that ischemic injuries cause major morbidity and mortality worldwide. Zebrafish embryos maintain function and homeostasis under low O2 by transitioning into a hypometabolic state, which is manifested by an arrest or a delay in development. Remarkably, zebrafish embryos can survive up to 50 hours in this hypometabolic state in complete absence of O2 (anoxia). Currently, the molecular mechanisms that initiate and maintain the hypometabolic state in zebrafish are unknown. Understanding these molecular mechanisms may reveal potential therapeutic targets for the prevention and treatment of ischemic injuries. We are currently using a multipronged approach to identify molecular mechanisms of hypometabolism in zebrafish embryos. A mass-spectrometry study examining metabolites whose levels change in anoxic conditions revealed a significant increase in the concentration of lactate – a molecule which was recently shown to bind to N-myc downstream-regulated gene (NDRG) to promote angiogenesis and proliferation in hypoxic cancer cells; suggesting a signaling role of lactate in cellular adaptation to low O2. Given these findings, we hypothesize that a lactate mediated signaling via NDRG under low O2 may be present in zebrafish embryos.
Cell-cell adhesion is essential for tissue growth and multicellular pattern formation, and crucial for cellular dynamics during embryogenesis and cancer progression. We present a mathematical model and computer simulation that captures the interplay between genetic regulation, expression of adhesion molecules, and differential cell adhesion. This continuous model demonstrates how dynamic changes in cell adhesion can drive classical cell sorting behaviors, cell intercalation in proliferating populations, and the involution of germ layer cells induced by a diffusing morphogen during gastrulation.