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Developmental biology - Circadian Rhythm

A New Gear In Life's Clock: Vitamin D

Vitamin D - the lack of it - triggers killifish embryos to become dormant...

New research from Portland State University finds vitamin D, or its lack, can trigger developmental timing changes in killifish embryos. Suggesting that vitamin D is critical in early embryo development within ALL vertebrates.

The killifish Austrofundulus limnaeus lives its entire life in ponds that fill with rain that later evaporates. This wet/dry climate operates on a seasonal schedule. To survive in such an uncertain environment, the fish evolved embryos that respond along two distinct paths. In one, the embryo grows to maturity. In the other, the embryo enters multiple states of dormancy, where all of its development stops. It can survive for months encased in dry mud — without oxygen or water.

How do they do that? Researchers at Portland State University focused their research on what regulates dormancy in A. limnaeus embryos and what mechanism turns embryo growth back on. To find the answer, a research team incubated killifish embryos at different temperatures to induce the two varying states - growth or dormancy. Then they analyzed killifish RNA during each of these states to identify any gene that on its own differentiates expression (function) to initiate growth or dormancy? The work was recently published in PNAS.
What they found was unexpected. An RNA analysis showed that while killifish are growing, vitamin D triggers normal development under environmental conditions that should favor a dormant state. On the other hand, if you inhibit vitamin D under environmental conditions that favor normal development, the killifish become dormant.

To test this vitamin D signal, the research team blocked vitamin D synthesis (which is the ability to produce chemical compounds from simpler molecules) in zebrafish embryos, who do not experience dormancy. Surpisingly, the embryos became dormant! This surprize result suggests that vitamin D may be critical across all vertebrate species. Researchers point out that similar receptors regulate dormancy in two other species: roundworms and fruit flies. This cross species similarity indicates vitamin D receptors function over a range of species throughout evolutionary history.
"This is a newly discovered role for vitamin D. What we're seeing is that vitamin D isn't just essential for the regulation of calcium, it plays an important role in critical life history transitions and may help us better understand the clock that regulates the life cycle."

Amie Romney, PhD candidate, Portland State University, and lead author of the study.

According to Jason Podrabsky PhD, professor of biology at Portland State University and Principal Investigator of the study, this discovery has implications in human health. Knowledge of what controls extreme physiological states - such as dormancy - helps us understand the molecular level of extreme cold shock, heart attack and stroke. An ability to induce dormancy, and not stop development, could be the first step in techniques to induce dormancy in humans, once considered impossible outside of science fiction.

Here we describe a molecular pathway that regulates dormancy in a vertebrate and highlights a mechanism that integrates environmental cues into a developmental program that has clear ecological and evolutionary significance. Further, we provide compelling evidence that vitamin D signaling is critical for normal vertebrate development and can induce a diapause-like arrest in embryos of zebrafish. The vitamin D receptor is homologous to nuclear receptors (NRs) that regulate dormancy in Caenorhabditis elegans and Drosophila. This conservation of function suggests a conserved role for hormones derived from 7-DHC and their associated NRs in the control of metabolic dormancy and major life history transitions in animals.

The mechanisms that integrate environmental signals into developmental programs remain largely uncharacterized. Nuclear receptors (NRs) are ligand-regulated transcription factors that orchestrate the expression of complex phenotypes. The vitamin D receptor (VDR) is an NR activated by 1a,25-dihydroxyvitamin D3 [1,25(OH)2D3], a hormone derived from 7-dehydrocholesterol (7-DHC). VDR signaling is best known for regulating calcium homeostasis in mammals, but recent evidence suggests a diversity of uncharacterized roles. In response to incubation temperature, embryos of the annual killifish Austrofundulus limnaeus can develop along two alternative trajectories: active development and diapause. These trajectories diverge early in development, from a biochemical, morphological, and physiological perspective. We manipulated incubation temperature to induce the two trajectories and profiled changes in gene expression using RNA sequencing and weighted gene coexpression network analysis. We report that transcripts involved in 1,25(OH)2D3 synthesis and signaling are expressed in a trajectory-specific manner. Furthermore, exposure of embryos to vitamin D3 analogs and ?4-dafachronic acid directs continuous development under diapause-inducing conditions. Conversely, blocking synthesis of 1,25(OH)2D3 induces diapause in A. limnaeus and a diapause-like state in zebrafish, suggesting vitamin D signaling is critical for normal vertebrate development. These data support vitamin D signaling as a molecular pathway that can regulate developmental trajectory and metabolic dormancy in a vertebrate. Interestingly, the VDR is homologous to the daf-12 and ecdysone NRs that regulate dormancy in Caenorhabditis elegans and Drosophila. We suggest that 7-DHC-derived hormones and their associated NRs represent a conserved pathway for the integration of environmental information into developmental programs associated with life history transitions in animals.

Amie L. T. Romney, Erin M. Davis, Meranda M. Corona, Josiah T. Wagner, and Jason E. Podrabsky.

Original data sets are available via the National Center for Biotechnology Information’s (NCBI) Sequence Read Archive, https://www.ncbi.nlm.nih.gov/sra (accession nos. SRX1032655, SRX1032657, SRX1032658, SRX1032664–SRX1032702; BioProject ID PRJNA272154).

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1804590115/-/DCSupplemental.

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Nov 26, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

Killifish embryos can survive multiple droughts by entering a dormant "sleep" induced by a drop in Vitamin D signals. Vitamin D appears to regulate dormancy in a vertebrate (killifish) while similarly inducing dormancy in two other species: roundworms and fruit flies. Image Credit: Wikimedia.org

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