例如:"lncRNA", "apoptosis", "WRKY"

Decreased Activity of the Ghrhr and Gh Promoters Causes Dominantly Inherited GH Deficiency in Humanized GH1 Mouse Models.

Endocrinology. 2019 Nov 01;160(11):2673-2691
Daisuke Ariyasu 1 , Emika Kubo 2 , Daisuke Higa 2 , Shinsuke Shibata 3 , Yutaka Takaoka 4 , Michihiko Sugimoto 2 , Kazunori Imaizumi 5 , Tomonobu Hasegawa 6 , Kimi Araki 7
Daisuke Ariyasu 1 , Emika Kubo 2 , Daisuke Higa 2 , Shinsuke Shibata 3 , Yutaka Takaoka 4 , Michihiko Sugimoto 2 , Kazunori Imaizumi 5 , Tomonobu Hasegawa 6 , Kimi Araki 7
+ et al

[No authors listed]

Author information
  • 1 Graduate School of Medicine, Keio University, Tokyo, Japan.
  • 2 Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan.
  • 3 Electron Microscope Laboratory, Keio University School of Medicine, Tokyo, Japan.
  • 4 Division of Medical Informatics and Bioinformatics, Kobe University Hospital, Hyogo, Japan.
  • 5 Department of Biochemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
  • 6 Keio University School of Medicine, Tokyo, Japan.
  • 7 Center for Metabolic Regulation of Healthy Aging, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.

摘要


Isolated growth hormone deficiency type II (IGHD2) is mainly caused by heterozygous splice-site mutations in intron 3 of the GH1 gene. A dominant-negative effect of the mutant GH lacking exon 3 on wild-type GH secretion has been proposed; however, the molecular mechanisms involved are elusive. To uncover the molecular systems underlying GH deficiency in IGHD2, we established IGHD2 model mice, which carry both wild-type and mutant copies of the human GH1 gene, replacing each of the endogenous mouse Gh loci. Our IGHD2 model mice exhibited growth retardation along with intact cellular architecture and mildly activated endoplasmic reticulum stress in the pituitary gland, caused by decreased GH-releasing hormone receptor (Ghrhr) and Gh gene promoter activities. Decreased Ghrhr and Gh promoter activities were likely caused by reduced levels of nuclear CREB3L2, which was demonstrated to stimulate Ghrhr and Gh promoter activity. To our knowledge, this is the first in vivo study to reveal a novel molecular mechanism of GH deficiency in IGHD2, representing a new paradigm that differs from widely accepted models.