Complex cooperative functions of heparan sulfate proteoglycans shape nervous system development in Caenorhabditis elegans.
Complex cooperative functions of heparan sulfate proteoglycans shape nervous system development in Caenorhabditis elegans.
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DOI：
10.1534/g3.114.012591
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发表时间：
2014-08-05
期刊：
影响因子：
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通讯作者：
Bülow HE
中科院分区：
文献类型：
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作者：
Díaz-Balzac CA;Lázaro-Peña MI;Tecle E;Gomez N;Bülow HE
神经系统的发育是一个复杂的过程，需要整合大量的分子线索来形成功能回路。许多线索是由硫酸肝素，一类线性糖胺聚糖多糖调节的。这些糖含有调节蛋白质相互作用的独特修饰模式。在秀丽隐杆线虫中，错误表达KAL-1/anosmin-1 （Kallmann综合征中的一种神经细胞粘附分子突变体）的同系物会导致AIY中间神经元中高度渗透、依赖硫酸肝素的轴突分支表型。在对该表型修饰因子的扩展前向遗传筛选中，我们发现了与HS生物合成和修饰相关的新基因和先前发现的基因中的等位基因，即木糖基转移酶sqv-6、HS-6- o -硫转移酶hst-6和HS-3- o -硫转移酶hst-3.2。细胞特异性救援实验表明，不同的HS生物合成和修饰酶可以由不同的组织非自主地提供细胞，以允许AIY的kal-1依赖性分支。此外，我们发现携带硫酸肝素链的硫酸肝素蛋白聚糖核心蛋白以高度冗余的方式在AIY神经元中介导kal-1依赖性分支。具体来说，lon-2/glypican和unc-52/perlecan在平行的遗传途径中起作用，并与sdn-1/syndecan表现出协同相互作用，介导kal-1功能。因为所有这些硫酸肝素核心蛋白已被证明在不同的组织中起作用，这些研究表明KAL-1/anosmin-1需要具有不同细胞来源的不同修饰模式的硫酸肝素才能发挥作用。我们的研究结果支持了一个模型，在这个模型中，硫酸肝素的三维支架通过复杂和合作的相互作用介导KAL-1/anosmin-1和细胞间的通信。此外，我们已经确定的基因可能有助于人类卡尔曼综合征的病因学。
The development of the nervous system is a complex process requiring the integration of numerous molecular cues to form functional circuits. Many cues are regulated by heparan sulfates, a class of linear glycosaminoglycan polysaccharides. These sugars contain distinct modification patterns that regulate protein–protein interactions. Misexpressing the homolog of KAL-1/anosmin-1, a neural cell adhesion molecule mutant in Kallmann syndrome, in Caenorhabditis elegans causes a highly penetrant, heparan sulfate–dependent axonal branching phenotype in AIY interneurons. In an extended forward genetic screen for modifiers of this phenotype, we identified alleles in new as well as previously identified genes involved in HS biosynthesis and modification, namely the xylosyltransferase sqv-6, the HS-6-O-sulfotransferase hst-6, and the HS-3-O-sulfotransferase hst-3.2. Cell-specific rescue experiments showed that different HS biosynthetic and modification enzymes can be provided cell-nonautonomously by different tissues to allow kal-1-dependent branching of AIY. In addition, we show that heparan sulfate proteoglycan core proteins that carry the heparan sulfate chains act genetically in a highly redundant fashion to mediate kal-1-dependent branching in AIY neurons. Specifically, lon-2/glypican and unc-52/perlecan act in parallel genetic pathways and display synergistic interactions with sdn-1/syndecan to mediate kal-1 function. Because all of these heparan sulfate core proteins have been shown to act in different tissues, these studies indicate that KAL-1/anosmin-1 requires heparan sulfate with distinct modification patterns of different cellular origin for function. Our results support a model in which a three-dimensional scaffold of heparan sulfate mediates KAL-1/anosmin-1 and intercellular communication through complex and cooperative interactions. In addition, the genes we have identified could contribute to the etiology of Kallmann syndrome in humans.