Functional analysis of endoplasmic reticulum stress-induced genes, NDRG1 and HERPUD1

Ndrg1是一种在多种应激和病理条件下诱导的细胞内蛋白，被认为与细胞的生长和分化有关。最近，人类NDRG1被发现是一个与遗传性运动和感觉神经病有关的基因-LOM(被归类为Charcot-Mirie-Tooth病4D型)，其特征是早发性周围神经病变。在这项研究中，我们产生了缺失Ndrg1的小鼠来分析它的功能。组织学分析显示，5周龄左右，Ndrg1基因缺失的小鼠坐骨神经变性，脱髓鞘。Ndrg1基因缺陷的小鼠表现出肌肉无力，尤其是后肢，但复杂的运动技能仍保留下来。在野生型小鼠中，NDRG1在雪旺细胞的胞浆中大量表达，而不是在髓鞘中表达。这些结果表明，NDRG1缺乏导致雪旺细胞功能障碍，提示NDRG1对于维持周围神经中的髓鞘是必不可少的。HERP已被分离为一种受致动脉粥样硬化物质同型半胱氨酸上调的基因。为了研究Herp的功能，我们分析了Herp缺失的小鼠的表型。测定荷瘤小鼠和野生型小鼠腹腔注射葡萄糖前后的血糖水平。建立小鼠局灶性脑缺血模型，比较两组小鼠脑梗塞的发展情况。HERP基因缺失的小鼠出生正常，没有表现出明显的异常。虽然他们的空腹血糖水平正常，但糖负荷后的恢复速度受到中度损害。由于对胰岛素的反应是正常的，HERP可能会影响胰腺细胞的胰岛素产生。HERP缺失型小鼠的脑梗塞体积明显大于野生型小鼠，说明HERP对脑缺血有保护作用。HERP在正常情况下似乎不是必需的，但在一些危急情况下可能起到保护作用。

Ndrg1 is an intracellular protein that is induced under a number of stress and pathological conditions, and it is thought to be associated with cell growth and differentiation. Recently, human NDRG1 was identified as a gene responsible for hereditary motor and sensory neuropathy-Lom (classified as Charcot-Mairie-Tooth disease type 4D), which is characterized by early-onset peripheral neuropathy. In this study, we generated mice lacking Ndrg1 to analyze its function. Histrogical analysis showed that the sciatic nerve of Ndrg1-defident mice degenerated with demyelination at about 5 weeks of age. Ndrg1-deficient mice showed muscle weakness, especially in the hind limbs, but complicated motor skills were retained. In wild-type mice, NDRG1 was abundantly expressed in the cytoplasm of Schwann cells rather than the myelin sheath. These results indicate that NDRG1 deficiency leads to Schwann cell dysfunction, suggesting that NDRG1 is essential for maintenance of the myelin sheaths in peripheral nerves.Herp has been isolated as a gene upregulated by atherogenic substance, homocysteine. To investigate the Herp function, we analyzed the phenotypes of Herp-null mice. The blood glucose levels were measured before and after intraperitoneal injection of glucose in Herp-null and wild-type mice. Focal cerebral ischemia was induced in these mice, and developments of cerebral infarction were compared. Herp-null mice were born normally, and exhibited no significant abnormalities. Although their fasting blood glucose levels were normal, the recovery speed after glucose load was moderately impaired. Since the response to insulin was normal, Herp may affect insulin production of pancreatic cells. The volumes of cerebral infarction in Herp-null mice were significantly larger than those in wild-type mice, indicating that Herp protects the brain under ischemia. Herp seems nonessential in normal conditions, but may play a protective role under some critical conditions.