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J. Biol. Chem., Vol. 283, Issue 23, 16004-16016, June 6, 2008

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Two Heparanase Splicing Variants with Distinct Properties Are Necessary in Early Xenopus Development^*

From the Hotchkiss Brain Institute, Department of Cell Biology and Anatomy, University of Calgary, Calgary, Alberta T2N 4N1, Canada

Heparanase is an endoglycosidase that cleaves heparan sulfate (HS) side chains from heparan sulfate proteoglycans (HSPGs) present in extracellular matrix and cell membranes. Although HSPGs have many functions during development, little is known of the role of the enzyme that degrades HS, heparanase. We cloned and characterized the expression of two heparanase splicing variants from Xenopus laevis and studied their function in early embryonic development. The heparanase gene (termed xHpa) spans over 15 kb and consists of at least 12 exons. The long heparanase (XHpaL) cDNA encodes a 531-amino acid protein, whereas the short splicing variant (XHpaS) results in a protein with the same open reading frame but missing 58 amino acids as a consequence of a skipped exon 4. Comparative studies of both isoforms using heterologous expression systems showed: 1) XHpaL is enzymatically active, whereas XHpaS is not; 2) XHpaL and XHpaS interact with heparin and HS; 3) both proteins traffic through the endoplasmic reticulum and Golgi apparatus, but XHpaL is secreted into the medium, whereas XHpaS remains associated with the membrane as a consequence of the loss of three glycosylation sites; 4) overexpression of XHpaS but not XHpaL increases cell adhesion of glioma cells to HS-coated surfaces; 5) XHpaL and XHpaS mRNA and protein levels vary as development progresses; 6) specific antisense knock-down of both XHpaL and XHpaS, but not XHpaL alone, results in failure of embryogenesis to proceed. Interestingly, rescue experiments suggest that the two heparanases regulate the same developmental processes, but via different mechanisms.

Received for publication, October 15, 2007 , and in revised form, February 21, 2008.

^* This work was supported in part by an operating grant from the Natural Sciences and Engineering Research Council of Canada and a University of Calgary Research grant. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a senior scholar award from the Alberta Heritage Foundation for Medical Research (AHFMR) and a Tier II Canada Research Chair in Developmental Neurobiology. To whom correspondence should be addressed: 3330 Hospital Dr., NW, Calgary, Alberta T2N 4N1, Canada. Tel.: 403-220-2539; Fax: 403-270-0737; E-mail: smcfarla{at}ucalgary.ca.

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