In vivo activities of heparan sulfate differentially modified by NDSTs during development.
In vivo activities of heparan sulfate differentially modified by NDSTs during development.
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硫酸乙酰肝素的体内活性在开发过程中受到 NDST 的差异修饰。
DOI：
10.1002/pgr2.17
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Nakato,Hiroshi
中科院分区：
文献类型：
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作者：
Nakato,Eriko;Baker,Sarah;Kinoshita-Toyoda,Akiko;Knudsen,Collin;Lu,Yi-Si;Takemura,Masahiko;Toyoda,Hidenao;Nakato,Hiroshi
硫酸乙酰肝素蛋白多糖(HSPGs)是发育过程中生长因子信号转导的辅助受体。众所周知，硫酸乙酰肝素(HS)链上硫酸盐基团的水平和模式，或HS的精细结构，对HSPG的功能有重要影响。另一方面，HS的其他结构特征，包括NS/NA结构域的组织，其生理意义仍有待阐明。HS结构域的蓝图主要由HSN-脱乙酰酶/N-磺基转移酶(NDSTs)控制。为了分析不同修饰的HS在体内的活性，我们建立了两个在无硫(SFL)基因座插入小鼠Ndst1(MNdst1)或Ndst2(MNdst2)的敲入(KI)果蝇株，即唯一的果蝇NDST。在这些KI细胞系中，mNDSTs从基因座开始表达，其表达水平和模式与内源基因相同。因此，Ndst1KI和Ndst2KI动物的表型反映了这些酶所形成的HS结构拯救突变的能力。值得注意的是，我们发现mNdst1完全挽救了sfl1的丢失。mNdst2显示出有限的拯救能力，尽管与hs inmNdst1KI相比，HS的硫酸盐化水平更高。我们的研究表明，与硫酸盐化水平无关，由NDST控制的额外HS结构特征在组织图案化过程中起着关键作用。
Heparan sulfate proteoglycans (HSPGs) serve as co‐receptors for growth factor signaling during development. It is well known that the level and patterns of sulfate groups of heparan sulfate (HS) chains, or HS fine structures, have a major impact on HSPG function. On the other hand, the physiological significance of other structural features of HS, including NS/NA domain organization, remains to be elucidated. A blueprint of the HS domain structures is mainly controlled by HSN‐deacetylase/N‐sulfotransferases (NDSTs). To analyze in vivo activities of differentially modified HS, we established two knock‐in (KI)Drosophilastrains with the insertion of mouseNdst1(mNdst1) orNdst2(mNdst2) in the locus ofsulfateless(sfl), the onlyDrosophilaNDST. In these KI lines, mNDSTs are expressed from thesfllocus, in the level and patterns identical to the endogenoussflgene. Thus, phenotypes ofNdst1KI andNdst2KI animals reflect the ability of HS structures made by these enzymes to rescuesflmutation. Remarkably, we found thatmNdst1completely rescued the loss ofsfl.mNdst2showed a limited rescue ability, despite a higher level of HS sulfation compared to HS inmNdst1KI. Our study suggests that independent of sulfation levels, additional HS structural features controlled by NDSTs play key roles during tissue patterning.