Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain-to-bone signaling pathway

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Our work is cross-disciplinary and combines cutting-edge approaches from comparative genomics, cell and developmental neurobiology, reverse genetics, bone physiology and evolutionary biology. Comparative analyses of vertebrate genomes reveal that the Pth4 is an ancient parathyroid hormone in vertebrates, but secondarily lost in eutherian mammals. Transgenic fish lines and loss-of-function experiments by targeted laser ablation enabled mapping a subset of hypothalamic Pth4-expressing neurons with axonal projections to the brainstem and spinal cord. These play an essential role in larval bone formation. We demonstrate that pth4 expression is directly regulated by Runx2, and that Pth4 can activate downstream cAMP signaling mediated by Pthr receptors. Gain-of-function experiments by pth4 ectopic expression in transgenic zebrafish demonstrate that Pth4 can alter calcium/phosphorus levels and affect expression of genes involved in phosphate homeostasis. Our findings culminate in a new model for the evolution of the PTH family roles in bone homeostasis in the context of the vertebrate transition from aquatic to terrestrial environments. We feel this manuscript will have broad interest not only for researchers of Bone Biology and Neurobiology, but also Developmental and Cell Biology, Comparative Genomics and Evolutionary Biology. Furthermore, I believe that the discovery and functional characterization of the Pth4 will has the potential to translate to novel therapeutic agents to treat human bone diseases.

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