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Prostaglandin signaling regulates renal multiciliated cell specification and maturation.

ABSTRACT: Multiciliated cells (MCCs) are specialized epithelia with apical bundles of motile cilia that direct fluid flow. MCC dysfunction is associated with human diseases of the respiratory, reproductive, and central nervous systems. Further, the appearance of renal MCCs has been cataloged in several kidney conditions, where their function is unknown. Despite their pivotal health importance, many aspects of MCC development remain poorly understood. Here, we utilized a chemical screen to identify molecules that affect MCC ontogeny in the zebrafish embryo kidney, and found prostaglandin signaling is essential both for renal MCC progenitor formation and terminal differentiation. Moreover, we show that prostaglandin activity is required downstream of the transcription factor ets variant 5a (etv5a) during MCC fate choice, where modulating prostaglandin E₂ (PGE₂) levels rescued MCC number. The discovery that prostaglandin signaling mediates renal MCC development has broad implications for other tissues, and could provide insight into a multitude of pathological states.

SUBMITTER: Marra AN

PROVIDER: S-EPMC6486750 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Prostaglandin signaling regulates renal multiciliated cell specification and maturation.

Marra Amanda N AN Adeeb Basma D BD Chambers Brooke E BE Drummond Bridgette E BE Ulrich Marisa M Addiego Amanda A Springer Meghan M Poureetezadi Shahram J SJ Chambers Joseph M JM Ronshaugen Matthew M Wingert Rebecca A RA

Proceedings of the National Academy of Sciences of the United States of America 20190404 17

Multiciliated cells (MCCs) are specialized epithelia with apical bundles of motile cilia that direct fluid flow. MCC dysfunction is associated with human diseases of the respiratory, reproductive, and central nervous systems. Further, the appearance of renal MCCs has been cataloged in several kidney conditions, where their function is unknown. Despite their pivotal health importance, many aspects of MCC development remain poorly understood. Here, we utilized a chemical screen to identify molecul ...[more]

PMID: 30948642

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Project description:BackgroundThe aberrant activation of Ras signaling is associated with human diseases including hematological malignancies and vascular disorders. So far the pathological roles of activated Ras signaling in hematopoiesis and vasculogenesis are largely unknown.MethodsA conditional Cre/loxP transgenic strategy was used to mediate the specific expression of a constitutively active form of human N-Ras in zebrafish endothelial and hematopoietic cells driven by the zebrafish lmo2 promoter. The expression of hematopoietic and endothelial marker genes was analyzed both via whole mount in situ hybridization (WISH) assay and real-time quantitative PCR (qPCR). The embryonic vascular morphogenesis was characterized both by living imaging and immunofluorescence on the sections with a confocal microscopy, and the number of endothelial cells in the embryos was quantified by flow cytometry. The functional analyses of the blood circulation were carried out by fluorescence microangiography assay and morpholino injection.ResultsIn the activated N-Ras transgenic embryos, the primitive hematopoiesis appeared normal, however, the definitive hematopoiesis of these embryos was completely absent. Further analysis of endothelial cell markers confirmed that transcription of arterial marker ephrinB2 was significantly decreased and expression of venous marker flt4 excessively increased, indicating the activated N-Ras signaling promotes the venous development at the expense of arteriogenesis during zebrafish embryogenesis. The activated N-Ras-expressing embryos showed atrophic axial arteries and expansive axial veins, leading to no definitive hematopoietic stem cell formation, the blood circulation failure and subsequently embryonic lethality.ConclusionsOur studies revealed for the first time that activated N-Ras signaling during the endothelial differentiation in vertebrates can disrupt the balance of arterial-venous specification, thus providing new insights into the pathogenesis of the congenital human vascular disease and tumorigenic angiogenesis.

Dataset Information

Prostaglandin signaling regulates renal multiciliated cell specification and maturation.

Publications

Prostaglandin signaling regulates renal multiciliated cell specification and maturation.

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