title: The tyrosine kinase receptor Tyro3 enhances lifespan and neuropeptide Y (Npy) neuron survival in the mouse anorexia (anx) mutation.
abstract: Severe appetite and weight loss define the eating disorder anorexia nervosa, and can also accompany the progression of some neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). Although acute loss of hypothalamic neurons that produce appetite-stimulating neuropeptide Y (Npy) and agouti-related peptide (Agrp) in adult mice or in mice homozygous for the anorexia (anx) mutation causes aphagia, our understanding of the factors that help maintain appetite regulatory circuitry is limited. Here we identify a mutation (C19T) that converts an arginine to a tryptophan (R7W) in the TYRO3 protein tyrosine kinase 3 (Tyro3) gene, which resides within theanxcritical interval, as contributing to the severity ofanxphenotypes. Our observation that, likeTyro3-/-mice,anx/anxmice exhibit abnormal secondary platelet aggregation suggested that the C19TTyro3variant might have functional consequences.Tyro3is expressed in the hypothalamus and other brain regions affected by theanxmutation, and its mRNA localization appeared abnormal inanx/anxbrains by postnatal day 19 (P19). The presence of wild-typeTyro3transgenes, but not anR7W-Tyro3transgene, doubled the weight and lifespans ofanx/anxmice and near-normal numbers of hypothalamic Npy-expressing neurons were present inTyro3-transgenicanx/anxmice at P19. Although no differences in R7W-Tyro3 signal sequence function or protein localization were discerniblein vitro, distribution of R7W-Tyro3 protein differed from that of Tyro3 protein in the cerebellum of transgenic wild-type mice. Thus, R7W-Tyro3 protein localization deficits are only detectablein vivoFurther analyses revealed that the C19TTyro3mutation is present in a few other mouse strains, and hence is not the causativeanxmutation, but rather ananxmodifier. Our work shows that Tyro3 has prosurvival roles in the appetite regulatory circuitry and could also provide useful insights towards the development of interventions targeting detrimental weight loss.
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Room 876, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.|Department of Molecular Genetics, University of Toronto, 1 King's Crescent, Toronto, ON M5S 1A8, Canada.
authors.forename: Dennis Y
authors.initials: DY
authors.lastname: Kim
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Room 876, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.|Department of Molecular Genetics, University of Toronto, 1 King's Crescent, Toronto, ON M5S 1A8, Canada.
authors.forename: Joanna
authors.initials: J
authors.lastname: Yu
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Room 876, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.|Department of Molecular Genetics, University of Toronto, 1 King's Crescent, Toronto, ON M5S 1A8, Canada.
authors.forename: Ryan K
authors.initials: RK
authors.lastname: Mui
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Room 876, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
authors.forename: Rieko
authors.initials: R
authors.lastname: Niibori
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Room 876, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.|Department of Molecular Genetics, University of Toronto, 1 King's Crescent, Toronto, ON M5S 1A8, Canada.
authors.forename: Hamza Bin
authors.initials: HB
authors.lastname: Taufique
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michaels Hospital, Toronto, ON M5B 1W8, Canada.|Canadian Blood Services, 67 College Street, Toronto, ON M5G 2M1, Canada.
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Aslam
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michaels Hospital, Toronto, ON M5B 1W8, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada.|Canadian Blood Services, 67 College Street, Toronto, ON M5G 2M1, Canada.
authors.forename: John W
authors.initials: JW
authors.lastname: Semple
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Room 876, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada cordes@lunenfeld.ca.|Department of Molecular Genetics, University of Toronto, 1 King's Crescent, Toronto, ON M5S 1A8, Canada.
authors.forename: Sabine P
authors.identifier: 0000-0002-3133-3655
authors.initials: SP
authors.lastname: Cordes
mesh_terms: D000818:Animals; D000855:Anorexia / Q000235:genetics / Q000473:pathology*; D002470:Cell Survival / Q000502:physiology*; D008136:Longevity / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009478:Neuropeptide Y / Q000502:physiology*; D010641:Phenotype; D017354:Point Mutation; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*
chemical_list: D009478:Neuropeptide Y; D020794:Receptor Protein-Tyrosine Kinases; C513478:Tyro3 protein, mouse
keywords: Appetite regulation; Eating disorder; Modifier; Neurodegeneration; Npy; RNA localization; Transgenic rescue