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Neuron. 2017 Dec 6;96(5):1055-1069.e6. doi: 10.1016/j.neuron.2017.10.025. Epub 2017 Nov 16.

The Wnt Inhibitor Apcdd1 Coordinates Vascular Remodeling and Barrier Maturation of Retinal Blood Vessels.

Author information

1
Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA; Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA.
2
Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
3
Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology & Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
4
Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA; Columbia Translational Neuroscience Initiative, Columbia University Medical Center, New York, NY 10032, USA.
5
Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA.
6
Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology & Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Pharmacology, Columbia University Medical Center, New York, NY 10032, USA; Columbia Translational Neuroscience Initiative, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: da191@cumc.columbia.edu.

Abstract

Coordinating angiogenesis with acquisition of tissue-specific properties in endothelial cells is essential for vascular function. In the retina, endothelial cells form a blood-retina barrier by virtue of tight junctions and low transcytosis. While the canonical Norrin/Fz4/Lrp5/6 pathway is essential for angiogenesis, vascular remodeling, and barrier maturation, how these diverse processes are coordinated remains poorly understood. Here we demonstrate that Apcdd1, a negative regulator of Wnt/β-catenin signaling, is expressed in retinal endothelial cells during angiogenesis and barrier formation. Apcdd1-deficient mice exhibit a transient increase in vessel density at ages P10-P12 due to delayed vessel pruning. Moreover, Apcdd1 mutant endothelial cells precociously form the paracellular component of the barrier. Conversely, mice that overexpress Apcdd1 in retina endothelial cells have reduced vessel density but increased paracellular barrier permeability. Apcdd1 thus serves to precisely modulate Wnt/Norrin signaling activity in the retinal endothelium and coordinate the timing of both vascular pruning and barrier maturation.

KEYWORDS:

Apcdd1; Caveolin-1; Claudin-5; Frizzled-4; Norrin; Occludin; Wnt/β-catenin signaling; angiogenesis; blood-retina barrier; tight junction; transcytosis; vascular pruning

PMID:
29154126
PMCID:
PMC5728434
[Available on 2018-12-06]
DOI:
10.1016/j.neuron.2017.10.025
[Indexed for MEDLINE]

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