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Abrogation of Prostaglandin E₂/EP4 Signaling Impairs the Development of rag1⁺ Lymphoid Precursors in the Thymus of Zebrafish Embryos¹

Eduardo J. Villablanca^*,, Anna Pistocchi, Felipe A. Court, Franco Cotelli, Claudio Bordignon^*, Miguel L. Allende^¶, Catia Traversari^|| and Vincenzo Russo^2,*

^* Cancer Gene Therapy Unit, Cancer Immunotherapy and Gene Therapy Program, Scientific Institute H. San Raffaele, Milan, Italy; International Ph.D. Program in Molecular Medicine, University "Vita-Salute" S.Raffaele, Milan, Italy; Department of Biology, University of Milan, Milan, Italy; Departamento de Ciencias Fisiológicas, Facultad de Ciencias Biológicas, Universidad Católica, Santiago, Chile; ^¶ Millennium Nucleus in Developmental Biology, Facultad de Ciencias, Universidad de Chile, Santiago, Chile; and ^|| MolMed SpA, Milan, Italy

PGE₂ is involved in a wide variety of physiological and pathological processes; however, deciphering its role in early mammalian development has been difficult due to the maternal contribution of PGE₂. To overcome this limitation we have investigated the role of PGE₂ during T cell development in zebrafish. In this study, we show that zebrafish ep4a, a PGE₂ receptor isoform of EP4, is expressed at 26 h postfertilization in the dorsal aorta-posterior cardinal vein joint region, which has a high homology with the mammal aorta-gonad-mesonephros area and where definitive hemopoiesis arises. Furthermore, it is expressed in the presumptive thymus rudiment by 48 h postfertilization. Supplementation of PGE₂ results in a strong increase in rag1 levels and cell proliferation in the thymus. In contrast, the inhibition of PGE₂ production, as well as EP4 blockade, abrogates the expression of rag1 in the thymus and that of the lymphoid precursor marker ikaros, not only in the dorsal aorta-posterior cardinal vein joint region but also in the newly identified caudal hemopoietic tissue without affecting early hemopoietic (scl, gata2) and erythropoietic (gata1) markers. These results identify ep4a as the earliest thymus marker and define a novel role for the PGE₂/EP4 pathway in controlling T cell precursor development in zebrafish.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from Fondazione Cariplo. M.L.A. was supported by grants from Fondo Nacional de Desarrollo Científico y Tecnológico (1031003), Iniciativa Científica Milenio (P02-050), and International Center for Genetic Engineering and Biotechnology (CRP/CHI03-03c).

² Address correspondence and reprint requests to Dr. Vincenzo Russo, Cancer Gene Therapy Unit, Scientific Institute S. Raffaele, Via Olgettina 58 Milan, Italy. E-mail address: v.russo{at}hsr.it

³ Abbreviations used in this paper: COX, cyclooxygenase; AGM, aorta-gonad-mesonephros; CHT, caudal hemopoietic tissue; DA-PCV, dorsal aorta-posterior cardinal vein; DN, double negative; DP, double positive; dpf, days postfertilization; hpf, hours postfertilization; HSC, hemopoietic stem cell; ICM, intermediate cell mass; inh, inhibitor; MO, morpholino oligonucleotide; PCNA, proliferating cell nuclear marker; WISH, whole in situ hybridization.