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14 Heparin-null Transgenic Mice are Unable to Store Certain Granule Proteases in Their Mast Cells

Although mast cell (MC) heparin is one of the most studied molecules in the body, the physiologic function of this glycosaminoglycan remains to be determined. Because N-deacetylase/N-sulfotransferase-2 (NDST-2) is essential for the biosynthesis of heparin, a homologous recombination approach was used to create transgenic mice which failed to express heparin. The resulting mice were viable and the chondroitin sulfate population of intraepithelial MCs that normally develop in the jejunal mucosa of mice during helminth infection contained mMCP-2+ granules which also appeared histochemically to be normal. In contrast, the population of MCs that developed in the skeletal muscle of the NDST-2-null mice lacked toluidine blue+or safranin+ granules. Moreover, these MCs failed to express appreciable amounts of mMCP-4, mMCP-5, and mMC-CPA protein. To address where the heparin-mediated defect resided, MCs were developed in vitro from the bone marrow of NDST-2 null mice. The resulting MCs contained high levels of the transcripts that encode mMCP-5, mMCP-6, and mMC-CPA whether or not these cells were subsequently cocultured with fibroblasts. Thus, disruption of heparin expression does not hinder the transcription of the protease genes. While the in vitro-differentiated MCs from NDST-2-null mice contained substantial amounts of mMCP-6 protein and histamine in their granules, these MCs were unable to store mMCP-5 and mMC-CPA protein. Thus, heparin is essential for the post-translational packaging of certain, but not all, positively charged proteases in MCs. [Supported by the VA and NIH (grants AI-23483 and HL-36110).]

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