The Redox Theory of Development.

Significance: The geological record shows that as atmospheric O2 levels increased, it concomitantly coincided with the evolution of metazoans. More complex, higher organisms contain a more cysteine-rich proteome, potentially as a means to regulate homeostatic responses in a more O2-rich environment. Regulation of redox-sensitive processes to control development is likely to be evolutionarily conserved. Recent Advances: During early embryonic development, the conceptus is exposed to varying levels of O2. Oxygen and redox-sensitive elements can be regulated to promote normal development, defined as changes to cellular mass, morphology, biochemistry, and function, suggesting that O2 is a developmental morphogen. During periods of O2 fluctuation, embryos are "reprogrammed," on the genomic and metabolic levels. Reprogramming imparts changes to particular redox couples (nodes) that would support specific post-translational modifications (PTMs), targeting the cysteine proteome to regulate protein function and development. Critical Issues: Major developmental events such as stem cell expansion, proliferation, differentiation, migration, and cell fate decisions are controlled through oxidative PTMs of cysteine-based redox nodes. As such, timely coordinated redox regulation of these events yields normal developmental outcomes and viable species reproduction. Disruption of normal redox signaling can produce adverse developmental outcomes. Future Directions: Furthering our understanding of the redox-sensitive processes/pathways, the nature of the regulatory PTMs involved in development and periods of activation/sensitivity to specific developmental pathways would greatly support the theory of redox regulation of development, and would also provide rationale and direction to more fully comprehend poor developmental outcomes, such as dysmorphogenesis, functional deficits, and preterm embryonic death.