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A Mutant Receptor Tyrosine Phosphatase, CD148, Causes Defects in Vascular Development

Nephrology Division and Center for Vascular Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232,¹ Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas 66160-0003,² Department of Cell Biology, Medical University of South Carolina, Charleston, South Carolina 29425,³ Immunex Corporation, Seattle, Washington 98101,⁶ Department of Molecular Genetics, Tokyo Metropolitan Institute of Gerontology, Tokyo 173,⁴ Institute of Development, Aging, and Cancer, Tohoku University, Sendai 980, Japan⁵

Received 9 July 2002/ Returned for modification 10 September 2002/ Accepted 11 December 2002

Vascularization defects in genetic recombinant mice have defined critical roles for a number of specific receptor tyrosine kinases. Here we evaluated whether an endothelium-expressed receptor tyrosine phosphatase, CD148 (DEP-1/PTP), participates in developmental vascularization. A mutant allele, CD148^CyGFP, was constructed to eliminate CD148 phosphatase activity by in-frame replacement of cytoplasmic sequences with enhanced green fluorescent protein sequences. Homozygous mutant mice died at midgestation, before embryonic day 11.5 (E11.5), with vascularization failure marked by growth retardation and disorganized vascular structures. Structural abnormalities were observed as early as E8.25 in the yolk sac, prior to the appearance of intraembryonic defects. Homozygous mutant mice displayed enlarged vessels comprised of endothelial cells expressing markers of early differentiation, including VEGFR2 (Flk1), Tal1/SCL, CD31, ephrin-B2, and Tie2, with notable lack of endoglin expression. Increased endothelial cell numbers and mitotic activity indices were demonstrated. At E9.5, homozygous mutant embryos showed homogeneously enlarged primitive vessels defective in vascular remodeling and branching, with impaired pericyte investment adjacent to endothelial structures, in similarity to endoglin-deficient embryos. Developing cardiac tissues showed expanded endocardial projections accompanied by defective endocardial cushion formation. These findings implicate a member of the receptor tyrosine phosphatase family, CD148, in developmental vascular organization and provide evidence that it regulates endothelial proliferation and endothelium-pericyte interactions.

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