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J. Biol. Chem., Vol. 279, Issue 18, 18920-18925, April 30, 2004

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In Vivo Hyaluronan Synthesis upon Expression of the Mammalian Hyaluronan Synthase Gene in Drosophila^*

Satomi Takeo, Momoko Fujise, Takuya Akiyama¶, Hiroko Habuchi, Naoki Itano, Takashi Matsuo, Toshiro Aigaki, Koji Kimata, and Hiroshi Nakato¶||

From the Department of Biological Sciences, Tokyo Metropolitan University, Hachioji-shi, Tokyo 192-0397, Japan, the Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan, and the ^¶Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota 55455

Hyaluronan (HA) is a large linear polymer of repeating disaccharides of glucuronic acid and GlcNAc. Although HA is widely distributed in vertebrate animals, it has not been found in invertebrates, including insect species. Insects utilize chitin, a repeating -1,4-linked homopolymer of GlcNAc, as a major component of their exoskeleton. Recent studies illustrate the similarities in the biosynthetic mechanisms of HA and chitin and suggest that HA synthase (HAS) and chitin synthase have evolved from a common ancestral molecule. Although the biochemical properties and in vivo functions of HAS proteins have been extensively studied, the molecular basis for HA biosynthesis is not completely understood. For example, it is currently not clear if proper chain elongation and secretion of HA require other components in addition to HAS. Here, we demonstrate that a non-HA-synthesizing animal, the fruit fly Drosophila melanogaster, can produce HA in vivo when a single HAS protein is introduced. Expression of the mouse HAS2 gene in Drosophila tissues by the Gal4/UAS (upstream activating sequence) system resulted in massive HA accumulation in the extracellular space and caused various morphological defects. These morphological abnormalities were ascribed to disordered cell-cell communications due to accumulation of HA rather than disruption of heparan sulfate synthesis. We also show that adult wings with HA can hold a high level of water. These findings demonstrate that organisms synthesizing chitin (but not HA) are capable of producing HA that is structurally and functionally relevant to that in mammals. The ability of insect cells to produce HA supports the idea that in vivo HA biosynthesis does not require molecules other than the HAS protein. An alternative model is that Drosophila cells use endogenous components of the chitin biosynthetic machinery to produce and secrete HA.

Received for publication, December 30, 2003 , and in revised form, February 9, 2004.

^* This work was supported in part by National Institutes of Health Grant HD042769 and Human Frontier Science Program Grant RGP0009/2003. 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.

^|| To whom correspondence should be addressed: Dept. of Genetics, Cell Biology, and Development, University of Minnesota, 6-160 Jackson Hall, 321 Church St. SE., Minneapolis, MN 55455. Tel.: 612-625-1727; Fax: 612-626-5652; E-mail: nakat003{at}umn.edu.

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