Abstract
In eutherian mammals, embryonic growth and survival is dependent on the formation of the placenta, an organ that facilitates the efficient exchange of oxygen, nutrients, and metabolic waste between the maternal and fetal blood supplies. Key to the placenta's function is the formation of its vascular labyrinth, a series of finely branched vessels whose molecular ontogeny remains largely undefined. In this report, we demonstrate that HOXA13 plays an essential role in labyrinth vessel formation. In the absence of HOXA13 function, placental endothelial cell morphology is altered, causing a loss in vessel wall integrity, edema of the embryonic blood vessels, and mid-gestational lethality. Microarray analysis of wild-type and mutant placentas revealed significant changes in endothelial gene expression profiles. Notably, pro-vascular genes, including Tie2 and Foxf1, exhibited reduced expression in the mutant endothelia, which also exhibited elevated expression of genes normally expressed in lymphatic or sinusoidal endothelia. ChIP analysis of HOXA13–DNA complexes in the placenta confirmed that HOXA13 binds the Tie2 and Foxf1 promoters in vivo. In vitro, HOXA13 binds sequences present in the Tie2 and Foxf1 promoters with high affinity (Kd = 27–42 nM) and HOXA13 can use these bound promoter regions to direct gene expression. Taken together, these findings demonstrate that HOXA13 directly regulates Tie2 and Foxf1 in the placental labyrinth endothelia, providing a functional explanation for the mid-gestational lethality exhibited by Hoxa13 mutant embryos as well as a novel transcriptional program necessary for the specification of the labyrinth vascular endothelia.
Highlights
For placental mammals, fetal development is contained in an intrauterine environment where the efficient exchange of oxygen, nutrients, and metabolic waste between the maternal and fetal blood supplies is facilitated by the placenta
We describe a novel role for HOXA13 in the developing placenta and identify both direct and indirect targets of HOXA13 functioning in the placental labyrinth endothelia
We identify a novel role for the transcription factor HOXA13 in formation of the placental vascular labyrinth
Summary
Fetal development is contained in an intrauterine environment where the efficient exchange of oxygen, nutrients, and metabolic waste between the maternal and fetal blood supplies is facilitated by the placenta. Central to the placenta’s function is its vascular labyrinth, a juxtaposed series of finely-branched blood vessels and trophoblasts that regulate nutrient and waste exchange while maintaining the separation of the maternal and fetal blood supplies [1]. Quantitation of HOXA13’s affinity for these promoter regions confirmed that HOXA13 binds these regions with high affinity and can utilize these bound DNA sequences to facilitate gene expression in vitro. Together these findings reveal a novel temporal and spatial domain for HOXA13 function in the developing embryo and identify a key transcriptional hierarchy necessary for the development of the placental vascular labyrinth
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