title: Activating transcription factor 6α is required for the vasopressin neuron system to maintain water balance under dehydration in male mice.
abstract: Activating transcription factor 6α (ATF6α) is a sensor of endoplasmic reticulum (ER) stress and increases the expression of ER chaperones and molecules related to the ER-associated degradation of unfolded/misfolded proteins. In this study, we used ATF6α knockout (ATF6α(-/-)) mice to clarify the role of ATF6α in the arginine vasopressin (AVP) neuron system. Although urine volumes were not different between ATF6α(-/-) and wild-type (ATF6α(+/+)) mice with access to water ad libitum, they were increased in ATF6α(-/-) mice compared with those in ATF6α(+/+) mice under intermittent water deprivation (WD) and accompanied by less urine AVP in ATF6α(-/-) mice. The mRNA expression of immunoglobulin heavy chain binding protein, an ER chaperone, was significantly increased in the supraoptic nucleus in ATF6α(+/+) but not ATF6α(-/-) mice after WD. Electron microscopic analyses demonstrated that the ER lumen of AVP neurons was more dilated in ATF6α(-/-) mice than in ATF6α(+/+) mice after WD. ATF6α(-/-) mice that were mated with mice possessing a mutation causing familial neurohypophysial diabetes insipidus (FNDI), which is characterized by progressive polyuria and AVP neuronal loss due to the accumulation of mutant AVP precursor in the ER, manifested increased urine volume under intermittent WD. The aggregate formation in the ER of AVP neurons was further impaired in FNDI/ATF6α(-/-) mice compared with that in FNDI mice, and AVP neuronal loss was accelerated in FNDI/ATF6α(-/-) mice under WD. These data suggest that ATF6α is required for the AVP neuron system to maintain water balance under dehydration.
authors.affiliation: Departments of Endocrinology and Diabetes (Y.A., D.H., W.L., Y.M., H.S., M.G., R.B., Y.S., Y.O., H.A.) and Pathology (N.A., M.T.), Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Institute of Immunology Co., Ltd (A.S.), 1198-4 Iwazo, Utsunomiya 321-0973, Japan; Institute for Genome Research (S.O.), University of Tokushima, Tokushima 770-8503, Japan; and Department of Biophysics (K.M.), Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Azuma
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hagiwara
authors.forename: Wenjun
authors.initials: W
authors.lastname: Lu
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Morishita
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Suga
authors.forename: Motomitsu
authors.initials: M
authors.lastname: Goto
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Banno
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Sugimura
authors.forename: Seiichi
authors.initials: S
authors.lastname: Oyadomari
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Mori
authors.forename: Akira
authors.initials: A
authors.lastname: Shiota
authors.forename: Naoya
authors.initials: N
authors.lastname: Asai
authors.forename: Masahide
authors.initials: M
authors.lastname: Takahashi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Oiso
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Arima
mesh_terms: D051702:Activating Transcription Factor 6 / Q000502:physiology*; D000818:Animals; D001127:Arginine Vasopressin / Q000502:physiology*; D003681:Dehydration / Q000503:physiopathology* / Q000652:urine; D020790:Diabetes Insipidus, Neurogenic / Q000503:physiopathology; D004721:Endoplasmic Reticulum / Q000502:physiology; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D056811:Unfolded Protein Response; D014882:Water-Electrolyte Balance
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D001127:Arginine Vasopressin