Human faces are variable; we look different from one another. Craniofacial disorders further increase facial variation. To understand craniofacial variation, and how it can be buffered, we analyzed the zebrafish mef2ca mutant. When this transcription factor encoding gene is mutated, zebrafish develop dramatically variable craniofacial phenotypes. Years of selective breeding for low and high penetrance of mutant phenotypes produced strains that are either resilient, or sensitive, to the mef2ca mutation. Here we compared gene expression between these strains, which revealed that selective breeding enriched for high and low mef2ca paralog expression in the low- and high-penetrance strains, respectively. We found that mef2ca paralog expression is variable in unselected wild-type zebrafish, motivating the hypothesis that heritable variation in paralog expression underlies mutant phenotype severity and variation. In support, mutagenizing the mef2ca paralogs, mef2aa, mef2b, mef2cb, and mef2d, demonstrated modular buffering by paralogs. Specifically, some paralogs buffer severity while others buffer variability. We present a novel, mechanistic model for phenotypic variation where variable, vestigial paralog expression buffers development. These studies are a major step forward in understanding the mechanisms of facial variation, including how some genetically resilient individuals can overcome a deleterious mutation.
The Notch pathway is a cell-cell communication system which is critical for many developmental processes, including craniofacial development. Notch receptor activation induces expression of several well-known canonical targets including those encoded by the hes and her genes in mammals and zebrafish, respectively. The function of these genes, individually and in combination, during craniofacial development is not well understood. Here, we used zebrafish genetics to investigate her9 and her6 gene function during craniofacial development. We found that her9 is required for osteoblasts to efficiently mineralize bone, while cartilage is largely unaffected. Strikingly, gene expression studies in her9 mutants indicate that although progenitor cells differentiate into osteoblasts at the appropriate time and place, they fail to efficiently lay down mineralized matrix. This mineralization role of her9 is likely independent of Notch activation. In contrast, her9 also functions redundantly with her6 downstream of Jagged1b-induced Notch activation during dorsoventral craniofacial patterning. These studies disentangle distinct and redundant her gene functions during craniofacial development, including an unexpected, Notch independent, requirement during bone mineralization.
Human faces are variable; we look different from one another. Craniofacial disorders further increase this variability. Here we used the zebrafish mef2ca mutant, which produces variable phenotypes, to understand craniofacial variation. Comparing different mef2ca alleles demonstrated that severity, measured by penetrance and expressivity, correlates with variation. Years of selective breeding for low and high penetrance produced strains that are either resilient, or sensitive, to the mef2ca mutation. Comparing these strains further demonstrates that severity correlates with variation. Gene expression studies indicated that selective breeding upregulated and downregulated mef2ca paralog expression in the low- and high-penetrance strains, respectively. We hypothesized that heritable paralog expression variation underlies mutant phenotype variation. In support, mutagenizing all mef2ca paralogs in the low-penetrance strain demonstrated modular buffering by paralogs. Specifically, some paralogs buffer severity while others buffer variability. We present a novel, mechanistic model for phenotypic variation where cryptic vestigial paralog expression modularly buffers development and contributes to evolution. These studies are a major step forward in understanding of the mechanisms of facial variation, including how some genetically resilient individuals can overcome a deleterious mutation.
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