The tyrosine kinase receptor Tyro3 enhances lifespan and neuropeptide Y (Npy) neuron survival in the mouse anorexia () mutation.

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 () 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 () gene, which resides within the critical interval, as contributing to the severity of phenotypes. Our observation that, like mice, mice exhibit abnormal secondary platelet aggregation suggested that the C19T variant might have functional consequences. is expressed in the hypothalamus and other brain regions affected by the mutation, and its mRNA localization appeared abnormal in brains by postnatal day 19 (P19). The presence of wild-type transgenes, but not an transgene, doubled the weight and lifespans of mice and near-normal numbers of hypothalamic Npy-expressing neurons were present in -transgenic mice at P19. Although no differences in R7W-Tyro3 signal sequence function or protein localization were discernible , 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 detectable Further analyses revealed that the C19T mutation is present in a few other mouse strains, and hence is not the causative mutation, but rather an modifier. 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.