Regulation of zebrafish fin regeneration by vitamin D signaling

Abstract

Background: Vitamin D is an essential nutrient that has long been known to regulate skeletal growth and integrity. In models of major appendage regeneration, treatment with vitamin D analogs has been reported to improve aspects of zebrafish fin regeneration in specific disease or gene misexpression contexts, but also to disrupt pattern in regenerating salamander limbs. Recently, we reported strong mitogenic roles for vitamin D signaling in several zebrafish tissues throughout life stages, including epidermal cells and osteoblasts of adult fins. To our knowledge, molecular genetic approaches to dissect vitamin D function in appendage regeneration have not been described. Results: Using a knock-in GFP reporter for the expression of the vitamin D target gene and negative regulator cyp24a1, we identified active vitamin D signaling in adult zebrafish fins during tissue homeostasis and regeneration.Transgenic expression of cyp24a1 or a dominant-negative vitamin D receptor (VDR) inhibited regeneration of amputated fins, whereas global vitamin D treatment accelerated regeneration. Using tissue regeneration enhancer elements, we found that local enhancement of VDR expression could improve regeneration with low doses of a vitamin D analog.Conclusions: Vitamin D signaling enhances the efficacy of fin regeneration in zebrafish.

Skeletal Biology and Disease Modeling in Zebrafish

“…(261) Likewise, vitD receptor inhibition suppressed fin regeneration, whereas vitD analogue treatment promoted fin regeneration. (262) In vivo compound screening with larval zebrafish revealed dose-dependent increases in the formation of mineralized bone following vitD and calcitriol administration. (263,264) Furthermore, diabetic zebrafish treated with paricalcitol, a vitD analog, showed improved bone regeneration and mineralization due to enhanced osteoblast differentiation and insulin expression.…”

Identification of enhancer regulatory elements that direct epicardial gene expression during zebrafish heart regeneration

“…Generation of transgenic animals and/or mutant animals is essential to validate TREEs, which have been described and validated in many contexts, including zebrafish hearts, zebrafish and killifish fins, and Drosophila imaginal discs (Begeman et al, 2020;Goldman et al, 2017;Harris et al, 2016;Kang et al, 2016;Pfefferli and Jazwinska, 2017;Wang et al, 2020). The discovery of specific regulatory sequences that underlie regeneration programs can reveal candidate upstream and downstream factors in regeneration, while also providing tools with which to manipulate regeneration (Chen et al, 2020;Kang et al, 2016;Sugimoto et al, 2017;van Duijvenboden et al, 2019).…”

Identification of enhancer regulatory elements that direct epicardial gene expression during zebrafish heart regeneration

“…Generation of transgenic animals and/or mutant animals is essential to validate TREEs, which have been described and validated in many contexts including zebrafish hearts, zebrafish and killifish fins, and Drosophila imaginal discs (Begeman et al, 2020; Goldman et al, 2017; Harris et al, 2016; Kang et al, 2016; Pfefferli and Jazwinska, 2017; Wang et al, 2020). The discovery of specific regulatory sequences that underlie regeneration programs can reveal candidate upstream and downstream factors in regeneration, while also providing tools to manipulate regeneration (Chen et al, 2020; Kang et al, 2016; Sugimoto et al, 2017; van Duijvenboden et al, 2019).…”