University of Huddersfield Repository Combinatorial Roles of Heparan Sulfate Proteoglycans and Heparan Sulfates in Caenorhabditis elegans Neural Development
University of Huddersfield Repository Combinatorial Roles of Heparan Sulfate Proteoglycans and Heparan Sulfates in Caenorhabditis elegans Neural Development
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哈德斯菲尔德大学知识库硫酸乙酰肝素蛋白聚糖和硫酸乙酰肝素在秀丽隐杆线虫神经发育中的组合作用
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通讯作者：
I. Hayakawa
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作者：
H. Kigoshi;I. Hayakawa
硫酸乙酰肝素蛋白聚糖 (HSPG) 在所有后生动物的发育和成体生理学中发挥着关键作用。大多数已知的 HSPG 分子相互作用都归因于结构高度复杂的硫酸乙酰肝素 (HS) 聚糖。然而，特定的 HSPG（例如多糖蛋白聚糖）是否含有与另一种 HSPG（例如磷脂酰肌醇蛋白聚糖）不同的 HS 修饰，在很大程度上仍未得到解决。在这里，线虫的神经模型首次用于证明体内特定生物过程中特定 HSPG 和 HS 修饰之间的关系。 HSPG 对于雌雄同体特异性神经元 (HSN) 的迁移至关重要，因为多个 HSPG 的基因消除会导致 80% 的 HSN 迁移缺陷。 HSPG 的基因消除效应是相加的，这表明迁移神经元和基质中存在多个 HSPG，并行作用以支持神经元迁移。遗传分析表明，syndecan / sdn-1 和 HS 6-O-磺基转移酶 hst-6 在线性信号传导途径中发挥作用，磷脂酰肌醇蛋白聚糖 / lon-2 和 HS 2-O-磺基转移酶 hst-2 在与 sdn-1 和 hst-6 平行的途径中一起发挥作用。这些结果表明核心蛋白特异性 HS 修饰对于 HSN 迁移至关重要。在秀丽隐杆线虫中，不同HS修饰的核心蛋白特异性可能部分地在编码HSPG和HS修饰酶的基因的组织特异性表达水平上受到调节。遗传分析表明，HS 修饰存在微妙的平衡，消除受损遗传背景中的一种 HS 修饰酶会导致整体表型发生显着变化。考虑到 HS 作为正常发育和疾病中细胞信号传导的关键调节因子，这些发现非常重要。
Heparan sulfate proteoglycans (HSPGs) play critical roles in the development and adult physiology of all metazoan organisms. Most of the known molecular interactions of HSPGs are attributed to the structurally highly complex heparan sulfate (HS) glycans. However, whether a specific HSPG (such as syndecan) contains HS modifications that differ from another HSPG (such as glypican) has remained largely unresolved. Here, a neural model in C. elegans is used to demonstrate for the first time the relationship between specific HSPGs and HS modifications in a defined biological process in vivo. HSPGs are critical for the migration of hermaphrodite specific neurons (HSNs) as genetic elimination of multiple HSPGs leads to 80% defect of HSN migration. The effects of genetic elimination of HSPGs are additive, suggesting that multiple HSPGs, present in the migrating neuron and in the matrix, act in parallel to support neuron migration. Genetic analyses suggest that syndecan / sdn-1 and HS 6-O-sulfotransferase , hst-6 , function in a linear signaling pathway and glypican / lon-2 and HS 2-O- sulfotransferase , hst-2 , function together in a pathway that is parallel to sdn-1 and hst-6 . These results suggest core protein specific HS modifications that are critical for HSN migration. In C. elegans , the core protein specificity of distinct HS modifications may be in part regulated at the level of tissue specific expression of genes encoding for HSPGs and HS modifying enzymes. Genetic analysis reveals that there is a delicate balance of HS modifications and eliminating one HS modifying enzyme in a compromised genetic background leads to significant changes in the overall phenotype. These findings are of importance with the view of HS as a critical regulator of cell signaling in normal development and disease.