Optimizing the mouse to sift sequence for function

embryos, suggesting that UDP-GIcDH activi.'y is absolutely required for WG activity. However, patterning of the embryonic epidermis requires hedge- bog (bh) as well as wg. Becau~ the two signaling pathways are cross- regulated by a complex feedback loop, it is difficult to .separate their activities in the epidermis. This poten- tial complication led Hacker et aL 1 to examine the relationship between UDP-GlcDH activity and WG signal- ing in other embryonic tissues where WG act"on is independent of HH. They discovered that loss of UDP- GIcDH activity resulted in stomato- gastric nervous system (SNS) defects similar to those found in partial loss- of-function ug- animals. But, the SNS defects were not as severe as those in embryos lacking all u,g activity. Mild wg- phenotypes were also observed in the midgut and Malpighian tubules of animals devoid of UDP-GIcDH. These findings argue that glycos- aminoglycans enhance WG activity, but are not absolutely required for signaling. If a tripartate complex is assembled on tile cell surface, it is likely that the proteoglycan func- tions as a regulatory component, perhaps altering the affinity of WG for the receptor. Together, the biochemical and genetic studies suggest that WG activ- ity is regulated extracellularly. In this regard, we note that WG can function either as a direct signal or fong-mnge morphogen, depending on die tis- sue 17. There are two general ways in which this process can be controlled. One is to modulate the concentration gradient of the ligand, the other is to adjust the affinity of receptor-ligand binding, Proteoglycans might Jure'don in either mechanism, Othc~r growth fa~xor signaling path- ways are also regulated by proteogly- mns in vivo. Preliminary observations indicate that FGF signaling is disrupted in UDP-GlcDH deficient embryos, These mutant embryos have develop- mental defects reminiscent of the phenotypes found in embryos lack- ing a functional FGF receptor (X. Lin, A. Miche "lson and N. Perrimon, unpub- lished). In contrast, embryonic DPP signaling is not affected by loss of UDP-GIcDH. Nevertheless proteogly- cans do regulate DPP signaling, at least in some cells.Jackson etal. 4 have found fllat dallycan regulate dppactivity in a tissue-specific manner, dallyencodes an integral membrane, heparan sullhte proteoglycan of the glypican family. Mutations in dally enhance dpp mu- tant phenotypes in the eye, antenna and genital discs, while the same dally mutations suppress dpp defects in the wing. So, why is DPP signaling not disrupted in glycosaminoglycan- deficient embryos? Pefllaps dallydoes not participate in embryonic DPP sig- naling. Alternatively, DPP, like its vertebrate homolop TGF-[3, might bind to file protein core of the proteo- glycan. Cleady, the story of proteogly- cans and growth factors is just begin- ning to unfold and a host of questions remain. Future studies promise to provide some exciting answers. Acknowledgements We thank members of the Perrimon laboratory for sharing unpublished results, J. Tumbull for useful comments, and R. Skinner for his generous help in preparing Fig. 1. References I Hacker, U.. Lin, X. and Perrimon, N. Development (in press) 2 Binari, R.C. etaL(1997) Development 124, 2623-2632 ,3 Haerry, T.E., Heslip, T.R., Marsh, J.L. and O'Conner, M.B. Lk, w, lopment (in press) 4 Jackmn, S.M. el ai. (1997) IX, wdopment 124, 4113-4120 5 Klingensmith, J. and Nus.~, R. (1994) Dev. BioL 166, 396-414 6 Moron, R.T., Brown, J.D. and Tortes, M. (I¢Y-)7J 7)'eJ~ds Genel. 13, 157-162 7 Perrimon, N., Engstrom, L. and Mahowald, A.P. (1989) Genetics 121, 333-352 8 Kjell~n, L and Hndahl, U. (1991) Atom. Rev. Biocbem. 60, 443--475 9 Reichsman F., Smith, L. and Cumberledge, S. (1996)J. Cell Biol. 135, 819--827 !0 Bradley, R.S. and Brown, A.M.C (1990) tLllBOJ. 9, 156%1575 II Burrus, L.W. and McMahon. A.P. (1995) Exp. Cell Res. 220, 363-373 12 Kispert, A. el al. (1996) Detz, fopmenr 122, 3627-3637 13 Moscatelli, D. (1987) J. Cell Physiol. 131, 123-130 14 Klagsbrun, M. and Baird, A. (1991) Cell67, 229-231 15 Ix~pez-Casillas, F.. Payne, H.M.. Andres, J.L. and Massague, J. (1994) J. Cell Biol. 24, 557-568 16 Schlessinger, J,, Lax, I. and Lerrln'lon, M. (1995) Cell83, 357-360 17 Zecca, M., Basler, K. and Stmhl, G. (1996) Cell 87, 833-844 18 Winter, W.T., Amott, S.. Isaac, D.H. and Atkins, E.D.T. (1978) L Mol. Biol. 125, 1-19 19 Mulloy, B,, Fo~ter, MJ., Jones, c. and Davies, D.B. (1993) Biocbem..l. 293, 849--858