Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Development. 2012 Aug;139(15):2730-9. doi: 10.1242/dev.079236. Epub 2012 Jun 28.
Glycosaminoglycans (GAGs) play a central role in embryonic development by regulating the movement and signaling of morphogens. We have previously demonstrated that GAGs are the co-receptors for Fgf10 signaling in the lacrimal gland epithelium, but their function in the Fgf10-producing periocular mesenchyme is still poorly understood. In this study, we have generated a mesenchymal ablation of UDP-glucose dehydrogenase (Ugdh), an essential biosynthetic enzyme for GAGs. Although Fgf10 RNA is expressed normally in the periocular mesenchyme, Ugdh mutation leads to excessive dispersion of Fgf10 protein, which fails to elicit an FGF signaling response or budding morphogenesis in the presumptive lacrimal gland epithelium. This is supported by genetic rescue experiments in which the Ugdh lacrimal gland defect is ameliorated by constitutive Ras activation in the epithelium but not in the mesenchyme. We further show that lacrimal gland development requires the mesenchymal expression of the heparan sulfate N-sulfation genes Ndst1 and Ndst2 but not the 6-O and 2-O-sulfation genes Hs6st1, Hs6st2 and Hs2st. Taken together, these results demonstrate that mesenchymal GAG controls lacrimal gland induction by restricting the diffusion of Fgf10.
糖胺聚糖 (GAGs) 通过调节形态发生素的运动和信号转导，在胚胎发育中发挥核心作用。我们之前已经证明 GAGs 是泪腺上皮中 Fgf10 信号的共受体，但它们在产生 Fgf10 的眶周间质中的功能仍知之甚少。在这项研究中，我们生成了 UDP-葡萄糖脱氢酶 (Ugdh) 的间质缺失，Ugdh 是 GAGs 的必需生物合成酶。尽管眶周间质中正常表达 Fgf10 RNA，但 Ugdh 突变导致 Fgf10 蛋白过度分散，无法在假定的泪腺上皮中引发 FGF 信号反应或芽生形态发生。这得到了遗传挽救实验的支持，其中上皮细胞中组成型 Ras 激活可改善 Ugdh 泪腺缺陷，但间质中则不行。我们进一步表明，泪腺发育需要间质表达肝素硫酸盐 N-硫酸化基因 Ndst1 和 Ndst2，但不需要 6-O 和 2-O-硫酸化基因 Hs6st1、Hs6st2 和 Hs2st。总之，这些结果表明，间质 GAG 通过限制 Fgf10 的扩散来控制泪腺的诱导。
