Tlx acts as a proangiogenic switch by regulating extracellular assembly of fibronectin matrices in retinal astrocytes
Akiyoshi Uemura, … , Ruth T. Yu, Shin-Ichi Nishikawa
Akiyoshi Uemura, … , Ruth T. Yu, Shin-Ichi Nishikawa
Published February 1, 2006
Citation Information: J Clin Invest. 2006;116(2):369-377. https://doi.org/10.1172/JCI25964.
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Tlx acts as a proangiogenic switch by regulating extracellular assembly of fibronectin matrices in retinal astrocytes

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.

Authors

Akiyoshi Uemura, Sentaro Kusuhara, Stanley J. Wiegand, Ruth T. Yu, Shin-Ichi Nishikawa

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Tlx regulates formation of proangiogenic scaffolds by controlling extrac...
Tlx regulates formation of proangiogenic scaffolds by controlling extracellular deposition of fibronectin matrices in retinal astrocytes. (A and E) Whole-mount ISH for VEGF (A) or fibronectin (E) in P7 retinas of Tlx–/– mice. The lower panels are magnifications of ISH (black) with immunostaining for PDGFRα (white). In contrast to the retained VEGF expression over the astrocyte network, fibronectin is expressed only in a small subset of astrocytes in Tlx–/– retina. OD, optic disc. (B) Whole-mount immunostaining for PECAM-1 in P16 Tlx–/– retinal cups 48 hours after intraocular injections of control Fc (upper panels) or VEGF Trap (lower panels). Right panels are the higher magnifications of hyaloid vessels shown in left panels. Persistent hyaloid vessels and their sprouts in Tlx–/– eyes regress by neutralization of VEGF signals. (C and D) Immunostaining for PECAM-1 (green) and GFAP (red) in P14 retina of Tlx–/– mouse. Ectopic vessels derived from hyaloids target retinal astrocytes (C) but are not guided by the pre-existing astrocyte networks (D). (F and G) Immunostaining for fibronectin (green) and PDGFRα (red) in Tlx+/– (upper panels) and Tlx–/– (lower panels) P7 retinas. In the astrocyte networks of Tlx–/– retinas, fibronectin proteins are detected only in a punctate manner (F). Note the retention of fibronectin proteins in perinuclear cytoplasmic regions of Tlx–/– astrocytes (G). Magnification, ×126 (upper panels of A and E), ×400 (lower panels of A and E), ×32 (B, left panels), ×100 (B, right panels), ×150 (C), ×630 (D), ×200 (F), ×1260 (G).