Platelet-Derived Growth Factor A Heparin-Binding Splice Isoform of Analysis of Mice Lacking the

he development of multicellular organisms requires cell-cellinteractions. Some of these depend on soluble paracrine li-gandsthatarereleasedfromcellsinordertobindtoreceptorsonneighboringcellsandtherebyelicitlocalcontrolofcellmigration,proliferation, death, and differentiation. The outcome for the in-dividual cell depends on the identity and local concentration ofthe signaling molecules, as well as their cognate receptors, as ex-emplifiedbymorphogensoftheHedgehog,transforminggrowthfactor beta (TGF-), and Wnt families. The distribution of theactive ligands in gradients or depots in the extracellular space isalsoimportant.Forexample,thedistributionofvascularendothe-lialgrowthfactorA(VEGF-A)ingradientsisnecessaryforpropermigration of so-called endothelial tip cells, which spearhead an-giogenic sprouts, and for the formation of a correctly patternedandfunctionalvasculature(1,2).Growthfactorgradientsmaybecreatedthroughcell-type-specificandpolarizedproteinsecretion,by binding to the extracellular matrix (ECM), and through un-equaldistributionofligand-modifyingenzymes(reviewedinref-erence 3) Thus, numerous processes contribute to the control ofthe distribution and bioavailability of growth factors and othersignaling molecules during embryonic development and otherphysiological and pathophysiological morphogenetic processes.Anumberofextracellularsignalingproteins,includinggrowthfactors, morphogens, cytokines, and enzymes (collectively re-ferred to as ligands), possess an ability to bind to heparin andheparan sulfate proteoglycans (HSPGs). In several cases, this in-teraction has been mapped to specific molecular domains andshowntodependonstretchesofpositivelycharged(basic)aminoacid residues present in the ligand and negatively charged groupspresent in heparin/HSPGs (reviewed in reference 4). A few basicaminoacidresiduesseemtobesufficienttoconferHSPGbinding.For example, mutagenesis of bone morphogenetic protein 4(BMP-4) in