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

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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.