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HOXA13 Is essential for placental vascular patterning and labyrinth endothelial specification.

Shaut CA, Keene DR, Sorensen LK, Li DY, Stadler HS - PLoS Genet. (2008)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon, United States of America.

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 (K(d) = 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.

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Sites of HOXA13 expression during placental labyrinth development.(A) HOXA13 is expressed in the endothelial progenitors in the E8.0 allantois. (B) HOXA13 expression is maintained in the endothelial progenitors during chorioallantoic fusion at E8.5. (C) Between E8.75 and E9.5, the HOXA13-expressing endothelial progenitors contribute to the developing feto-placental vessels, which mature to form the umbilical artery (UA), chorionic plate vessels, and the vessels contributing to the placental labyrinth (D). HOXA13 is not expressed in the developing umbilical vein (UV).
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pgen-1000073-g002: Sites of HOXA13 expression during placental labyrinth development.(A) HOXA13 is expressed in the endothelial progenitors in the E8.0 allantois. (B) HOXA13 expression is maintained in the endothelial progenitors during chorioallantoic fusion at E8.5. (C) Between E8.75 and E9.5, the HOXA13-expressing endothelial progenitors contribute to the developing feto-placental vessels, which mature to form the umbilical artery (UA), chorionic plate vessels, and the vessels contributing to the placental labyrinth (D). HOXA13 is not expressed in the developing umbilical vein (UV).

Mentions: Among the 39 murine Hox genes, only mutations in Hoxa13 cause mid-gestational lethality from embryonic day (E) 11–15.5 [27]–[29]. Initially, this phenotype was attributed to premature stenosis of the umbilical arteries [29]. Extensive analysis of the umbilical artery (UA) defect in Hoxa13 homozygous mutants revealed that only one of the two UAs exhibited complete stenosis from E11.5–15.5 (Figure 1A and 1B). This finding prompted the hypothesis that an additional defect must be contributing to the mid-gestational lethality. Because malformations of the heart and placenta are the most commonly cited reasons for mid-gestational lethality, we first examined whether Hoxa13 is expressed in the developing heart or placenta [30]–[34]. No HOXA13 expression was detected in the cardiac crescent; however, the earliest component of the placenta, the allantoic bud mesoderm, strongly expressed HOXA13 from E7.75 and maintained expression in the maturing allantois and developing labyrinth microvessels at E8.5 and E9.5 respectively (Figures 1C–1G and 2). At E10.5, HOXA13 expression was readily detected in the developing placental labyrinth (Figures 1H and 2) whereas the chorionic ectoderm exhibited little or no HOXA13 expression from E9.5 to E10.5 (Figures 1E–1H, 2). To note, the timing and occurrence of chorioallantoic fusion was unaffected by the loss of HOXA13 function (data not shown).


HOXA13 Is essential for placental vascular patterning and labyrinth endothelial specification.

Shaut CA, Keene DR, Sorensen LK, Li DY, Stadler HS - PLoS Genet. (2008)

Sites of HOXA13 expression during placental labyrinth development.(A) HOXA13 is expressed in the endothelial progenitors in the E8.0 allantois. (B) HOXA13 expression is maintained in the endothelial progenitors during chorioallantoic fusion at E8.5. (C) Between E8.75 and E9.5, the HOXA13-expressing endothelial progenitors contribute to the developing feto-placental vessels, which mature to form the umbilical artery (UA), chorionic plate vessels, and the vessels contributing to the placental labyrinth (D). HOXA13 is not expressed in the developing umbilical vein (UV).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2367452&req=5

pgen-1000073-g002: Sites of HOXA13 expression during placental labyrinth development.(A) HOXA13 is expressed in the endothelial progenitors in the E8.0 allantois. (B) HOXA13 expression is maintained in the endothelial progenitors during chorioallantoic fusion at E8.5. (C) Between E8.75 and E9.5, the HOXA13-expressing endothelial progenitors contribute to the developing feto-placental vessels, which mature to form the umbilical artery (UA), chorionic plate vessels, and the vessels contributing to the placental labyrinth (D). HOXA13 is not expressed in the developing umbilical vein (UV).
Mentions: Among the 39 murine Hox genes, only mutations in Hoxa13 cause mid-gestational lethality from embryonic day (E) 11–15.5 [27]–[29]. Initially, this phenotype was attributed to premature stenosis of the umbilical arteries [29]. Extensive analysis of the umbilical artery (UA) defect in Hoxa13 homozygous mutants revealed that only one of the two UAs exhibited complete stenosis from E11.5–15.5 (Figure 1A and 1B). This finding prompted the hypothesis that an additional defect must be contributing to the mid-gestational lethality. Because malformations of the heart and placenta are the most commonly cited reasons for mid-gestational lethality, we first examined whether Hoxa13 is expressed in the developing heart or placenta [30]–[34]. No HOXA13 expression was detected in the cardiac crescent; however, the earliest component of the placenta, the allantoic bud mesoderm, strongly expressed HOXA13 from E7.75 and maintained expression in the maturing allantois and developing labyrinth microvessels at E8.5 and E9.5 respectively (Figures 1C–1G and 2). At E10.5, HOXA13 expression was readily detected in the developing placental labyrinth (Figures 1H and 2) whereas the chorionic ectoderm exhibited little or no HOXA13 expression from E9.5 to E10.5 (Figures 1E–1H, 2). To note, the timing and occurrence of chorioallantoic fusion was unaffected by the loss of HOXA13 function (data not shown).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon, United States of America.

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 (K(d) = 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.

Show MeSH
Related in: MedlinePlus