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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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Analysis of endothelial cell migration and neovascularization in cultured placental primary arteries.(A, B), (D, E) Arterial sections from heterozygous control and homozygous mutants exhibit robust neovascularization and microvessel formation in vitro. Black boxes denote the sites examined by confocal microscopy to visualize migrating endothelia participating in microvessel formation. (C), (F) The loss of HOXA13 function does not affect the migration and contribution of HOXA13-expressing endothelia (green nuclei) to the developing microvessels. Note that the migrating endothelia co-express PECAM-1 (red signal). Bar is 25 µm.
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pgen-1000073-g007: Analysis of endothelial cell migration and neovascularization in cultured placental primary arteries.(A, B), (D, E) Arterial sections from heterozygous control and homozygous mutants exhibit robust neovascularization and microvessel formation in vitro. Black boxes denote the sites examined by confocal microscopy to visualize migrating endothelia participating in microvessel formation. (C), (F) The loss of HOXA13 function does not affect the migration and contribution of HOXA13-expressing endothelia (green nuclei) to the developing microvessels. Note that the migrating endothelia co-express PECAM-1 (red signal). Bar is 25 µm.

Mentions: Since defects in endothelial cell migration can also contribute to perturbations in vessel branching, we examined whether Hoxa13 mutant endothelia were competent to migrate and participate in de novo angiogenesis (Figure 7). A comparison of mutant and heterozygous control cultured arterial sections revealed comparable levels of neo-vessel production after five days of growth (Figure 7A and 7B and 7D and 7E). Characterization of the cells contributing to the neo-vessels revealed strong HOXA13 expression in the PECAM-1 positive endothelia in both heterozygous and homozygous mutant (Figure 7C and 7F). This result suggests that endothelial cell migration is not affected by the loss of HOXA13 function in the in vitro angiogenesis assay.


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

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

Analysis of endothelial cell migration and neovascularization in cultured placental primary arteries.(A, B), (D, E) Arterial sections from heterozygous control and homozygous mutants exhibit robust neovascularization and microvessel formation in vitro. Black boxes denote the sites examined by confocal microscopy to visualize migrating endothelia participating in microvessel formation. (C), (F) The loss of HOXA13 function does not affect the migration and contribution of HOXA13-expressing endothelia (green nuclei) to the developing microvessels. Note that the migrating endothelia co-express PECAM-1 (red signal). Bar is 25 µm.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1000073-g007: Analysis of endothelial cell migration and neovascularization in cultured placental primary arteries.(A, B), (D, E) Arterial sections from heterozygous control and homozygous mutants exhibit robust neovascularization and microvessel formation in vitro. Black boxes denote the sites examined by confocal microscopy to visualize migrating endothelia participating in microvessel formation. (C), (F) The loss of HOXA13 function does not affect the migration and contribution of HOXA13-expressing endothelia (green nuclei) to the developing microvessels. Note that the migrating endothelia co-express PECAM-1 (red signal). Bar is 25 µm.
Mentions: Since defects in endothelial cell migration can also contribute to perturbations in vessel branching, we examined whether Hoxa13 mutant endothelia were competent to migrate and participate in de novo angiogenesis (Figure 7). A comparison of mutant and heterozygous control cultured arterial sections revealed comparable levels of neo-vessel production after five days of growth (Figure 7A and 7B and 7D and 7E). Characterization of the cells contributing to the neo-vessels revealed strong HOXA13 expression in the PECAM-1 positive endothelia in both heterozygous and homozygous mutant (Figure 7C and 7F). This result suggests that endothelial cell migration is not affected by the loss of HOXA13 function in the in vitro angiogenesis assay.

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