Mouse Genetics Study of the Gret Gene in Transgenic Mice

• Main Authors: Hui-Wen Zhuang, 莊惠雯
• Other Authors: Ting-Fen Tsai
• Format: Others
• Language: zh-TW
• Published: 2008
• Online Access: http://ndltd.ncl.edu.tw/handle/85436891478571396821

碩士 === 國立陽明大學 === 生命科學暨基因體科學研究所 === 96 === The growth retardation (GRET) gene is an evolutionarily conserved gene with previously undefined function. Significantly, this gene is located within the chromosome 4q23-25 region where the genetic determinant(s) for longevity was mapped. We have previously generated a knockout mice with Gret systematically mutated in the whole body of mice. Our results revealed that deficiency of Gret protein in mice leads to severe growth retardation and shortened lifespan with pleiotropic phenotypes resembling those of human progeria (premature aging) syndromes. The early phenotypic characteristics of Gret knockout mice include reduced body weight, muscle atrophy and nerve degeneration. The later phenotypic effects of Gret deficiency include prominent eyes and protruding ears, lordokyphosis, osteopenis, abnormal pulmonary functions, opacity of the cornea, as well as skin atrophy and hair graying. We have generated the Gret transgenic mice driven by the RNA polymerase II (Pol II) promoter to study the effects of elevated levels of Gret protein on lifespan control and aging related phenotypes. No overt phenotypes related to morphology, growth and oxidative stress resistance were observed comparing the Gret transgenic and wild-type mice until 12-month old. Interestingly, our results revealed that the transgenic Gret protein can partially rescue the progeria phenotypes of the Gret knockout mice. This includes growth retardation, and skeletal muscle atrophy as illustrated by H&E pathological analyses of the GretTg/+; Gret-/- mice. In addition, our ultra-structural examination of transmission electron microscope (TEM) revealed that the transgenic Gret protein can also rescue the mitochondrial degeneration of cardio- and skeletal muscles, as well as the degeneration of myelin sheath of sciatic nerves obtained from the GretTg/+; Gret-/- mice. The Gret transgenic mice thus provide an animal model for the study of physiological pathway and molecular mechanism relevant to aging phenotypes and lifespan control.