Genetic ablation of Pth4 disrupts calcium-phosphate balance, bone development, and kidney transcriptome in teleosts

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Abstract
Parathyroid hormone 4 (Pth4) is an evolutionarily conserved member of the PTH family, expressed in hypothalamic neurons and lost in eutherian mammals. In order to elucidate its role in mineral homeostasis and skeletal development, a pth4 knockout ( pth4 KO ) zebrafish line was generated using CRISPR/Cas9 and transcriptomic profiling was conducted across six key tissues: brain, kidney, intestine, gills, scales, and bone. The results obtained demonstrated that the loss of Pth4 led to pronounced disturbances in calcium and phosphate homeostasis, skeletal deformities, and widespread tissue-specific transcriptional alterations. Notably, dysregulation of mineral regulatory genes— such as fgf23, phex , and slc34a1a was particularly evident in the kidney, suggesting disruption of the FGF23-Klotho axis. In parallel, differential expression of extracellular matrix genes ( col1a1a, col10a1a, col11a1 ) and matrix remodeling enzymes ( mmp9, mmp13a, mmp2 ) in bone and scales indicated impaired skeletal remodeling. Together, these findings highlight a pivotal role for Pth4 in the endocrine and local regulation of mineral metabolism and skeletal integrity, expanding our understanding of PTH family functions in vertebrate physiology.
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Funding Information
  • Agencia Estatal de Investigación (MCIN/AEI/10.13039/501100011033, AGL2017-89648P)
  • European Union

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