Chronic Hyponatremia Potentiates Innate Morphogenetic Mispatterning Through Dysfunction of Indolamine- and Catechol-Signaling Progenitors in Murine Limb Buds
June 20
Hyponatremia is the most prevalent electrolyte imbalance encountered in developmental and regenerative settings. Once regarded as clinically silent owing to presumed cellular adaptation, emerging evidence suggests that chronic hyponatremia (CHN) can precipitate structural anomalies, including cryptic morphogenetic defects. Nevertheless, the exact tissue-level phenotypes driven by CHN, their molecular underpinnings, and their reversibility remain unresolved. Accordingly, we sought to determine whether indolamine- and catechol-mediated paracrine signaling governs the innate morphogenetic deviations potentiated by CHN in a murine limb-bud culture model of inappropriate antidiuresis.
Using ex utero limb-bud explants engineered to maintain sustained reductions in extracellular Na⁺, we demonstrate that prolonged hyponatremia magnifies baseline mispatterning, as quantified by aberrant mesenchymal condensation and ectopic epithelial invagination in whole-mount optical projections. High-performance liquid chromatography revealed that tryptamine- and catechol-derived morphogens were markedly diminished in CHN explants relative to isotonic controls. Concomitantly, phosphorylation of extracellular signal-regulated kinase (ERK) within the apical ectodermal ridge was significantly attenuated under hyponatremic conditions.
Strikingly, restitution of physiological Na⁺ rapidly normalized condensation geometry, reinstated indolamine and catechol morphogen titers, and restored ERK phosphorylation to baseline. These observations underscore the necessity of correcting CHN during embryonic growth or tissue repair and highlight bioelectric–amine crosstalk as a tractable axis for therapeutic intervention aimed at safeguarding pattern fidelity during regeneration.