title: Fetal deficiency of lin28 programs life-long aberrations in growth and glucose metabolism.
abstract: LIN28A/B are RNA binding proteins implicated by genetic association studies in human growth and glucose metabolism. Mice with ectopic over-expression of Lin28a have shown related phenotypes. Here, we describe the first comprehensive analysis of the physiologic consequences of Lin28a and Lin28b deficiency in knockout (KO) mice. Lin28a/b-deficiency led to dwarfism starting at different ages, and compound gene deletions showed a cumulative dosage effect on organismal growth. Conditional gene deletion at specific developmental stages revealed that fetal but neither neonatal nor adult deficiency resulted in growth defects and aberrations in glucose metabolism. Tissue-specific KO mice implicated skeletal muscle-deficiency in the abnormal programming of adult growth and metabolism. The effects of Lin28b KO could be rescued by Tsc1 haplo-insufficiency in skeletal muscles. Our data implicate fetal expression of Lin28a/b in the regulation of life-long effects on metabolism and growth, and demonstrate that fetal Lin28b acts at least in part via mTORC1 signaling.
authors.affiliation: Stem Cell Transplantation Program, Stem Cell Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA; Harvard Stem Cell Institute, Boston, Massachusetts, USA.
authors.forename: Gen
authors.initials: G
authors.lastname: Shinoda
authors.forename: Ng
authors.initials: N
authors.lastname: Shyh-Chang
authors.forename: T Yvanka de
authors.initials: TY
authors.lastname: Soysa
authors.forename: Hao
authors.initials: H
authors.lastname: Zhu
authors.forename: Marc T
authors.initials: MT
authors.lastname: Seligson
authors.forename: Samar P
authors.initials: SP
authors.lastname: Shah
authors.forename: Nora
authors.initials: N
authors.lastname: Abo-Sido
authors.forename: Akiko
authors.initials: A
authors.lastname: Yabuuchi
authors.forename: John P
authors.initials: JP
authors.lastname: Hagan
authors.forename: Richard I
authors.initials: RI
authors.lastname: Gregory
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Eric G
authors.initials: EG
authors.lastname: Moss
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004392:Dwarfism / Q000235:genetics / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000378:metabolism; D015870:Gene Expression; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D048788:Growth and Development; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012737:Sex Factors; D015398:Signal Transduction
chemical_list: D004268:DNA-Binding Proteins; C488352:Lin-28 protein, mouse; C570876:Lin28b protein, mouse; D016601:RNA-Binding Proteins; D005947:Glucose
keywords: Diabetes; Dwarfism; Glucose metabolism; Growth; Lin28a; Lin28b; let-7; mTOR