The Caenorhabditis elegans HNF4α Homolog, NHR-31, Mediates Excretory Tube Growth and Function through Coordinate Regulation of the Vacuolar ATPase
The Caenorhabditis elegans HNF4α Homolog, NHR-31, Mediates Excretory Tube Growth and Function through Coordinate Regulation of the Vacuolar ATPase
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DOI：
10.1371/journal.pgen.1000553
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发表时间：
2009-07-01
期刊：
影响因子：
4.5
通讯作者：
Van Gilst, Marc R.
中科院分区：
文献类型：
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作者：
Hahn-Windgassen, Annett;Van Gilst, Marc R.
肝细胞核因子 4 (HNF4) 亚型的核受体与从蠕虫到人类等动物的许多发育和代谢功能有关；然而，该核受体亚家族所进行的全部生理活动还远未确定。我们发现，秀丽隐杆线虫核受体 NHR-31（哺乳动物 HNF4 受体的同源物）是控制线虫排泄细胞（一种充当秀丽隐杆线虫肾脏系统的多分支管状细胞）的生长和功能所必需的。幼虫特异性 RNAi 敲除 nhr-31 导致排泄细胞管长度方向显着的结构异常，包括靠近和远离细胞核的许多不受控制的生长区域。 nhr-31 RNAi 动物对离子应激的急性攻击敏感，这意味着排泄细胞的渗透压调节功能也受到损害。基因表达谱揭示了 nhr-31 在控制编码液泡 ATP 酶 (vATPase) 亚基的多个基因中具有令人惊讶的特定作用。这些 vATPase 基因的 RNAi 导致排泄细胞缺陷，类似于在 nhr-31 RNAi 动物中观察到的缺陷，表明 nhr-31 对排泄细胞生长的影响至少部分是通过 vATPase 的协调调节介导的。序列分析揭示了线虫和小鼠 vATPase 基因启动子中 HNF4 α 型结合位点的惊人富集，表明 HNF4 受体对 vATPase 的协调调节可能在哺乳动物中是保守的。我们的研究建立了一条调节排泄细胞生长的新途径，并揭示了 HNF4 型核受体在肾脏系统发育和功能中的新作用。
Nuclear receptors of the Hepatocyte Nuclear Factor-4 (HNF4) subtype have been linked to a host of developmental and metabolic functions in animals ranging from worms to humans; however, the full spectrum of physiological activities carried out by this nuclear receptor subfamily is far from established. We have found that the Caenorhabditis elegans nuclear receptor NHR-31, a homolog of mammalian HNF4 receptors, is required for controlling the growth and function of the nematode excretory cell, a multi-branched tubular cell that acts as the C. elegans renal system. Larval specific RNAi knockdown of nhr-31 led to significant structural abnormalities along the length of the excretory cell canal, including numerous regions of uncontrolled growth at sites near to and distant from the cell nucleus. nhr-31 RNAi animals were sensitive to acute challenge with ionic stress, implying that the osmoregulatory function of the excretory cell was also compromised. Gene expression profiling revealed a surprisingly specific role for nhr-31 in the control of multiple genes that encode subunits of the vacuolar ATPase (vATPase). RNAi of these vATPase genes resulted in excretory cell defects similar to those observed in nhr-31 RNAi animals, demonstrating that the influence of nhr-31 on excretory cell growth is mediated, at least in part, through coordinate regulation of the vATPase. Sequence analysis revealed a stunning enrichment of HNF4 alpha type binding sites in the promoters of both C. elegans and mouse vATPase genes, arguing that coordinate regulation of the vATPase by HNF4 receptors is likely to be conserved in mammals. Our study establishes a new pathway for regulation of excretory cell growth and reveals a novel role for HNF4-type nuclear receptors in the development and function of a renal system.