Vitamin D globally accelerates growth and regeneration in zebrafish

Animals possess control mechanisms to synchronize organ and organismal size during growth, to maintain tissue integrity through homeostatic cell proliferation, and to counter major injury with regeneration. A principal research goal is to elucidate mitogenic triggers that underlie these mechanisms. Here, from a large-scale in vivo chemical screen, we discovered that analogues of the essential nutrient vitamin D potently activate heart muscle cell division in larval zebrafish. Unexpectedly, loss- and gain-of-function methods to modulate vitamin D signaling altered metabolic and cell cycle gene expression in zebrafish larvae and dictated rates of organismal growth. Systemic vitamin D treatment sharply increased in vivo cell proliferation in a variety of adult cell types including cardiomyocytes, hepatocytes, osteoblasts, cardiac mesothelium, skin and corneal epithelium, and retina, and enhanced injury-induced heart and appendage regeneration. Our experiments identify vitamin D signaling as a broad growth- and regeneration-initiating influence throughout the life stages of a vertebrate model system. Adult zebrafish were injected with vehicle or alfacalcidol daily for three days. Hearts were extracted 24 hours after the last injection. Total RNA were harvested using TRIzol reagent, digested with DNaseI, and purified with Zymo Quick-RNA MiniPrep kit. Libraries were prepared and sequenced using an Illumina HiSeq2000 at the Duke Center for Genomic and Computational Biology.