Pallerla Srinivas R, Pan Yi, Zhang Xin, Esko Jeffrey D, Grobe Kay
Institut für Allgemeine Zoologie und Genetik, Westfälische Wilhelms-Universität Münster, Münster, Germany.
Dev Dyn. 2007 Feb;236(2):556-63. doi: 10.1002/dvdy.21038.
Disruption of heparan sulfate (HS) synthesis in vertebrate development causes malformations that are composites of those caused by mutations of multiple HS binding growth factors and morphogens. We previously reported severe developmental defects of the forebrain and the skull in mutant mice bearing a targeted disruption of the heparan sulfate-generating enzyme GlcNAc N-deacetylase/GlcN N-sulfotransferase 1 (Ndst1). Here, we further characterize the molecular mechanisms leading to frontonasal dysplasia in Ndst1 mutant embryos and describe additional malformations, including impaired spinal and cranial neural tube fusion and skeletal abnormalities. Of the numerous proteins that bind HS, we show that impaired fibroblast growth factor, Hedgehog, and Wnt function may contribute to some of these phenotypes. Our findings, therefore, suggest that defects in HS synthesis may contribute to multifactor types of congenital developmental defects in humans, including neural tube defects.
在脊椎动物发育过程中，硫酸乙酰肝素（HS）合成的破坏会导致畸形，这些畸形是由多种HS结合生长因子和形态发生素的突变所引起的畸形的复合体。我们之前报道过，携带硫酸乙酰肝素生成酶N-乙酰葡糖胺N-脱乙酰酶/N-葡糖胺N-磺基转移酶1（Ndst1）靶向破坏的突变小鼠存在严重的前脑和颅骨发育缺陷。在此，我们进一步阐述导致Ndst1突变胚胎额鼻发育异常的分子机制，并描述其他畸形，包括脊髓和颅神经管融合受损以及骨骼异常。在众多与HS结合的蛋白质中，我们发现成纤维细胞生长因子、刺猬蛋白和Wnt功能受损可能导致了其中一些表型。因此，我们的研究结果表明，HS合成缺陷可能导致人类多种先天性发育缺陷，包括神经管缺陷。
