title: Endoplasmic reticulum stress in vasopressin neurons of familial diabetes insipidus model mice: aggregate formation and mRNA poly(A) tail shortening.
abstract: The immunoglobulin heavy chain binding protein (BiP) is an endoplasmic reticulum (ER) chaperone, which binds to newly synthesized secretory and transmembrane proteins to facilitate protein folding. BiP mRNA is expressed in the arginine vasopressin (AVP) neurons in the supraoptic nucleus of wild-type mice even in basal conditions, and the expression levels increase in response to dehydration. These data suggest that AVP neurons are subjected to ER stress. Familial neurohypophysial diabetes insipidus (FNDI) is caused by mutations in the gene locus of AVP. The mutant proteins could accumulate in the ER and possibly increase ER stress in the AVP neurons. We bred mice possessing a mutation causing FNDI, which manifested progressive polyuria, as do the patients with FNDI. Electron microscopic analyses demonstrated that aggregates accumulated in the ER of AVP neurons in FNDI mice. Despite polyuria, which could potentially induce dehydration, AVP mRNA expression was decreased in the supraoptic nucleus, and the AVP mRNA poly(A) tail length was shortened in FNDI mice compared with wild-type mice. Incubation of hypothalamic explants of wild-type mice with ER stressors caused shortening of the poly(A) tail length of AVP mRNA, accompanied by decreases in the expression. These data revealed a mechanism by which ER stress decreases poly(A) tail length of AVP mRNA, and this reduces the load of unfolded proteins that form the aggregates in ER of the AVP neurons in FNDI mice.
authors.affiliation: H. Arima: 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. arima105@med.nagoya-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Arima
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Morishita
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hagiwara
authors.forename: Masayuki
authors.initials: M
authors.lastname: Hayashi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Oiso
mesh_terms: D000818:Animals; D020790:Diabetes Insipidus, Neurogenic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009474:Neurons / Q000473:pathology*; D017510:Protein Folding; D012333:RNA, Messenger / Q000235:genetics; D014667:Vasopressins / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D014667:Vasopressins