MicroRNAs Establish Uniform Traits during the Architecture of Vertebrate Embryos

Abstract

SUMMARY Proper functioning of an organism requires cells and tissues to behave in uniform, well-organized ways. How this optimum of phenotypes is achieved during the development of vertebrates is unclear. Here, we carried out a multifaceted and single-cell resolution screen of zebrafish embryonic blood vessels upon mutagenesis of single and multi-gene miRNA families. We found that embryos lacking particular miRNA-dependent signaling pathways develop a vascular trait similar to wild type, but with a profound increase in phenotypic heterogeneity. Aberrant trait variance in miRNA mutant embryos uniquely sensitizes their vascular system to environmental perturbations. We discovered a previously unrecognized role for specific vertebrate miRNAs to protect tissue development against phenotypic variability. This discovery marks an important advance in our comprehension of how miRNAs function in the development of higher organisms.

MicroRNA-mediated control of developmental lymphangiogenesis

“…In some cases, miRNA mutants have been shown to exert minor influences on organ development that are exacerbated under certain environmental stress condition. For example, animals lacking members of the miR-139 or miR-24 endothelial miRNA families display mild or no phenotype, but they do display greater phenotypic variability upon angiogenic stress, high temperature, or hypoxic conditions, suggesting these endothelial miRNAs help limiting phenotypic variation in the vascular system (Kasper et al, 2017). A recent systematic study of Drosophila miRNA knockouts reported that 80% of miRNA mutants display at least one observable defect throughout the course of development from embryogenesis to adulthood, indicating that despite their relatively modest phenotypes and variable degree of severity most Drosophila miRNA mutants do display some abnormalities (Chen et al, 2014).…”

A framework for understanding the roles of miRNAs in animal development

“…In C. elegans, mir-34;mir-83 double mutants have a low penetrance defect in gonad morphogenesis that is significantly enhanced if animals are subjected to temperature oscillations (Burke et al, 2015). More recently, mir-139 and mir-24 have been shown to be required for robust vasculature development in zebrafish (Kasper et al, 2017). This was evidenced not only in the increased sensitivity of animals lacking these miRNAs to diverse stressors, but also in the increase in variance of some of the observed traits, even under standard conditions.…”

MicroRNAs Make a Difference in Cardiovascular Robustness

“…Finally, what are the sources of variation that are buffered by miRNAs? As now shown in zebrafish, as well as invertebrate models, environmental differences are one plausible source (Cassidy et al, 2013; Kasper et al, 2017; Ren and Ambros, 2015; Yatsenko and Shcherbata, 2014). Another source, at least in Drosophila , is the natural variation in genome sequence between individuals (Cassidy et al, 2013).…”

“…In this issue of Developmental Cell , Stefania Nicoli and colleagues describe how several miRNAs reduce phenotypic variation in zebrafish lab populations, and may thus canalize developmental traits related to the cardiovasculature (Kasper et al, 2017). The authors identified miR-139, miR-223, and the miR-24 family, which were highly enriched in cardiovascular endothelia of zebrafish embryos.…”