Lin X, Buff E M, Perrimon N, Michelson A M
Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
Development. 1999 Sep;126(17):3715-23. doi: 10.1242/dev.126.17.3715.
The Drosophila sugarless and sulfateless genes encode enzymes required for the biosynthesis of heparan sulfate glycosaminoglycans. Biochemical studies have shown that heparan sulfate glycosaminoglycans are involved in signaling by fibroblast growth factor receptors, but evidence for such a requirement in an intact organism has not been available. We now demonstrate that sugarless and sulfateless mutant embryos have phenotypes similar to those lacking the functions of two Drosophila fibroblast growth factor receptors, Heartless and Breathless. Moreover, both Heartless- and Breathless-dependent MAPK activation is significantly reduced in embryos which fail to synthesize heparan sulfate glycosaminoglycans. Consistent with an involvement of Sulfateless and Sugarless in fibroblast growth factor receptor signaling, a constitutively activated form of Heartless partially rescues sugarless and sulfateless mutants, and dosage-sensitive interactions occur between heartless and the heparan sulfate glycosaminoglycan biosynthetic enzyme genes. We also find that overexpression of Branchless, the Breathless ligand, can partially overcome the requirement of Sugarless and Sulfateless for Breathless activity. These results provide the first genetic evidence that heparan sulfate glycosaminoglycans are essential for fibroblast growth factor receptor signaling in a well defined developmental context, and support a model in which heparan sulfate glycosaminoglycans facilitate fibroblast growth factor ligand and/or ligand-receptor oligomerization.
果蝇无糖基因和无硫酸化基因编码硫酸乙酰肝素糖胺聚糖生物合成所需的酶。生化研究表明，硫酸乙酰肝素糖胺聚糖参与成纤维细胞生长因子受体的信号传导，但在完整生物体中这种需求的证据尚未可得。我们现在证明，无糖和无硫酸化突变胚胎具有与缺乏两种果蝇成纤维细胞生长因子受体（“无情”和“气喘吁吁”）功能的胚胎相似的表型。此外，在无法合成硫酸乙酰肝素糖胺聚糖的胚胎中，依赖“无情”和“气喘吁吁”的MAPK激活显著降低。与无硫酸化基因和无糖基因参与成纤维细胞生长因子受体信号传导一致，一种组成型激活形式的“无情”部分挽救了无糖和无硫酸化突变体，并且“无情”与硫酸乙酰肝素糖胺聚糖生物合成酶基因之间存在剂量敏感相互作用。我们还发现，“气喘吁吁”的配体“无分支”的过表达可以部分克服无糖基因和无硫酸化基因对“气喘吁吁”活性的需求。这些结果提供了首个遗传学证据，表明在明确的发育背景下，硫酸乙酰肝素糖胺聚糖对成纤维细胞生长因子受体信号传导至关重要，并支持一个模型，即硫酸乙酰肝素糖胺聚糖促进成纤维细胞生长因子配体和/或配体-受体寡聚化。
