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PMID:16424942

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Citation

Uemura, A, Kusuhara, S, Wiegand, SJ, Yu, RT and Nishikawa, S (2006) Tlx acts as a proangiogenic switch by regulating extracellular assembly of fibronectin matrices in retinal astrocytes. J. Clin. Invest. 116:369-77

Abstract

In response to hypoxia, hypoxia-inducible factors act as the primary proangiogenic triggers by regulating transcription levels of target genes, including VEGF. However, little is known about the specific factors that control other components of the angiogenic process, particularly formation of matrix scaffolds that promote adhesion and migration of endothelial cells. We show that in the postnatal mouse retina, the orphan nuclear receptor tailless (Tlx) is strongly expressed in the proangiogenic astrocytes, which secrete VEGF and fibronectin. Tlx expression by retinal astrocytes is controlled by oxygen concentration and rapidly downregulated upon contact with blood vessels. In mice null for Tlx, retinal astrocytes maintain VEGF expression; however, the extracellular assembly of fibronectin matrices by astrocytes is severely impaired, leading to defective scaffold formation and a complete failure of normal retinal vascular development. This work identifies Tlx as an essential component of the molecular network involved in the hypoxia-inducible proangiogenic switch in retinal astrocytes.

Links

PubMed PMC1332029 Online version:10.1172/JCI25964

Keywords

Animals; Antigens, CD31/metabolism; Astrocytes/cytology; Astrocytes/metabolism; Collagen Type IV/metabolism; Extracellular Matrix/metabolism; Fibronectins/metabolism; Glial Fibrillary Acidic Protein/genetics; Glial Fibrillary Acidic Protein/metabolism; Immunohistochemistry; In Situ Hybridization; Mice; Mice, Knockout; Neovascularization, Physiologic; Oxygen/metabolism; Receptor, Platelet-Derived Growth Factor alpha/genetics; Receptor, Platelet-Derived Growth Factor alpha/metabolism; Receptors, Cytoplasmic and Nuclear/genetics; Receptors, Cytoplasmic and Nuclear/metabolism; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism; Retina/cytology; Retina/metabolism; Vascular Endothelial Growth Factor A/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:ITB1

acts_upstream_of_or_within

GO:0002042: cell migration involved in sprouting angiogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(EMAPA:36520)
  • results_in_movement_of:(CL:0000071)

Seeded From UniProt

complete

MOUSE:NR2E1

acts_upstream_of_or_within

GO:0030198: extracellular matrix organization

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2176560

P

  • occurs_in:(EMAPA:17168)

Seeded From UniProt

complete

MOUSE:NR2E1

acts_upstream_of_or_within

GO:0051128: regulation of cellular component organization

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2176560

P

  • regulates_o_occurs_in:(EMAPA:17168)

Seeded From UniProt

complete

MOUSE:NR2E1

acts_upstream_of_or_within

GO:0045766: positive regulation of angiogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2176560

P

  • regulates_o_results_in_formation_of:(EMAPA:36520)
  • regulates_o_has_participant:(CL:0000127)

Seeded From UniProt

complete

MOUSE:NR2E1

acts_upstream_of_or_within

GO:0090049: regulation of cell migration involved in sprouting angiogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2176560

P

  • regulates_o_occurs_in:(EMAPA:17168)
  • regulates_o_results_in_movement_of:(CL:0000071)

Seeded From UniProt

complete


See also

References

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