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Non–heparan sulfate‐binding interactions of endostatin/collagen XVIII in murine development
Author(s) -
Rychkova Natalia,
Stahl Sonja,
Gaetzner Sabine,
Felbor Ute
Publication year - 2005
Publication title -
developmental dynamics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.634
H-Index - 141
eISSN - 1097-0177
pISSN - 1058-8388
DOI - 10.1002/dvdy.20222
Subject(s) - endostatin , biology , heparan sulfate , microbiology and biotechnology , glycosaminoglycan , biochemistry , cancer research , angiogenesis
Knobloch syndrome is characterized by a congenital generalized eye disease and cranial defect. Pathogenic mutations preferentially lead to a deletion or functional alteration of collagen XVIII's most C‐terminal endostatin domain. Endostatin can be released from collagen XVIII and is a potent inhibitor of angiogenesis and tumor growth. We show differential expression of binding partners for endostatin, vascular endothelial growth factor (VEGF), and the collagen XV endostatin homologue in murine embryonal development using a set of alkaline phosphatase fusion proteins. Consistent with the human phenotype, vascular mesenchyme in the developing eye was identified as endostatin's primary target. While endostatin predominantly bound to blood vessels, the VEGF164 affinity probe labeled nonvascular tissues such as forebrain, hindbrain, the optic nerve, and the surface ectoderm of the future cornea. Strikingly increased staining specificity was observed with a non–heparin/heparan sulfate‐binding endostatin probe. In contrast, elimination of the heparan sulfate binding site from VEGF led to complete loss of binding. The collagen XV endostatin homologue showed a highly restricted binding pattern. Oligomerization with endogenous endostatin was ruled out by use of collagen XVIII knockout mice. Our data provide strong evidence that collagen XVIII's C‐terminal endostatin domain harbors a prominent tissue‐binding site and that binding can occur in the absence of heparan sulfates in situ. Developmental Dynamics 232:399–407, 2005. © 2004 Wiley‐Liss, Inc.