title: Role of the Atg9a gene in intrauterine growth and survival of fetal mice.
abstract: Autophagy is activated by environment unfavorable for survival and requires Atg9a protein. Mice heterozygous for p57(Kip2), devoid of the imprinted paternal allele (p57(Kip2+/-)), are known to develop hypertension during pregnancy. To determine whether fetal Atg9a is involved in the intrauterine survival and growth of fetal mice, this study was performed on Atg9a heterozygous (Atg9a(+/-)) pregnant mice with and without p57(Kip2+/-). The pregnant mice heterozygous for both knockout alleles of Atg9a and p57(Kip2) (Atg9a(+/-)/p57(Kip2+/-)), but not those heterozygous for Atg9a alone, developed hypertension during pregnancy. Placental expression of Atg9a mRNA was significantly decreased in the Atg9a(-/-) mice compared to Atg9a(+/-) or Atg9a(+/+) mice. The Atg9a(-/-) fetal mice exhibited significantly retarded growth and were more likely to die in utero compared to Atg9a(+/+) and Atg9a(+/-) fetal mice. Growth retardation was observed in the presence of maternal hypertension in Atg9a(-/-) fetal mice. These results suggest that Atg9a(-/-) fetal mice from pregnant dams heterozygous for both knockout alleles of Atg9a and p57(Kip2) are more susceptible to hypertensive stress than fetuses with intact autophagic machinery.
authors.affiliation: Department of Obstetrics, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kojima
authors.affiliation: Department of Obstetrics, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan. Electronic address: taka0197@med.hokudai.ac.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Obstetrics, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Rina
authors.initials: R
authors.lastname: Akaishi
authors.affiliation: Department of Obstetrics, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Itsuko
authors.initials: I
authors.lastname: Furuta
authors.affiliation: Laboratory of Host Defense, WPI Immunology Frontier Research Centre, Osaka University, Suita 565-0871, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Saitoh
authors.affiliation: Division of Developmental Genomics, Department of Maternal-Fetal Biology, National Centre for Child Health and Development, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakabayashi
authors.affiliation: Department of Molecular and Cellular Biology and Laboratory of Embryonic and Genetic Engineering, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.affiliation: Division of Cell Proliferation, Tohoku University School of Medicine, Sendai 980-8575, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: Laboratory of Host Defense, WPI Immunology Frontier Research Centre, Osaka University, Suita 565-0871, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: Department of Obstetrics, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Hisanori
authors.initials: H
authors.lastname: Minakami
mesh_terms: D000483:Alleles; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D000071183:Autophagy-Related Proteins; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics / Q000378:metabolism; D005260:Female; D047109:Fetal Development / Q000235:genetics*; D005317:Fetal Growth Retardation / Q000235:genetics* / Q000378:metabolism; D006579:Heterozygote; D046110:Hypertension, Pregnancy-Induced / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C549015:Atg9A protein, mouse; D000071183:Autophagy-Related Proteins; C493965:Cdkn1c protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; D008565:Membrane Proteins; D033921:Vesicular Transport Proteins
keywords: Autophagy; Fetal growth restriction; Hypertension; Hypoxia; Intrauterine fetal death