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cdx4 mutants fail to specify blood progenitors and can be rescued by multiple hox genes

Abstract

Organogenesis is dependent on the formation of distinct cell types within the embryo. Important to this process are the hox genes, which are believed to confer positional identities to cells along the anteroposterior axis1,2,3. Here, we have identified the caudal-related gene cdx4 as the locus mutated in kugelig (kgg), a zebrafish mutant with an early defect in haematopoiesis that is associated with abnormal anteroposterior patterning and aberrant hox gene expression. The blood deficiency in kgg embryos can be rescued by overexpressing hoxb7a or hoxa9a but not hoxb8a, indicating that the haematopoietic defect results from perturbations in specific hox genes. Furthermore, the haematopoietic defect in kgg mutants is not rescued by scl overexpression, suggesting that cdx4 and hox genes act to make the posterior mesoderm competent for blood development. Overexpression of cdx4 during zebrafish development or in mouse embryonic stem cells induces blood formation and alters hox gene expression. Taken together, these findings demonstrate that cdx4 regulates hox genes and is necessary for the specification of haematopoietic cell fate during vertebrate embryogenesis.

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Figure 1: Abnormal blood and kidney development in kggtv205mutants.
Figure 2: Isolation of the kgg gene and developmental expression of cdx4.
Figure 3: Overexpression of cdx4 induces ectopic blood and rescues kggtv205 embryos.
Figure 4: The haematopoietic defect in kggtv205 mutants is associated with abnormal hox gene expression and can be rescued by hoxb6b, hoxb7a and hoxa9a.
Figure 5: Cdx4 alters hox gene expression in zebrafish and mouse cells and induces blood development in embryoid bodies.

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Acknowledgements

We would like to thank members of the Zon laboratory, B. Paw and S. Orkin for critical reading of this manuscript. We also thank K. Humphries for HoxB4 retrovirus, H. G. Frohnhöfer for kgg mutants, J. Postlethwait and A. Amores for genomic sequences, and members of the zebrafish community for gifts of cDNAs. L.I.Z is an Investigator of the Howard Hughes Medical Institute. This work was supported by Legal Sea Foods, the Grousbeck family and grants from the NIH.

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Correspondence to Leonard I. Zon.

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Davidson, A., Ernst, P., Wang, Y. et al. cdx4 mutants fail to specify blood progenitors and can be rescued by multiple hox genes. Nature 425, 300–306 (2003). https://doi.org/10.1038/nature01973

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