Tyrosine-protein kinase receptor TYRO3 precursor (EC 2.7.10.1) (Tyrosine-protein kinase BYK) (Tyrosine-protein kinase DTK) (Tyrosine-protein kinase RSE) (Tyrosine-protein kinase SKY) (Tyrosine-protein kinase TIF) [BYK] [DTK] [RSE] [SKY] [TIF]
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 ([i]anx[/i]) 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 ([i]Tyro3[/i]) gene, which resides within the [i]anx[/i] critical interval, as contributing to the severity of [i]anx[/i] phenotypes. Our observation that, like [i]Tyro3 [/i] mice, [i]anx/anx[/i] mice exhibit abnormal secondary platelet aggregation suggested that the C19T [i]Tyro3[/i] variant might have functional consequences. [i]Tyro3[/i] is expressed in the hypothalamus and other brain regions affected by the [i]anx[/i] mutation, and its mRNA localization appeared abnormal in [i]anx/anx[/i] brains by postnatal day 19 (P19). The presence of wild-type [i]Tyro3[/i] transgenes, but not an [i]R7W-Tyro3[/i] transgene, doubled the weight and lifespans of [i]anx/anx[/i] mice and near-normal numbers of hypothalamic Npy-expressing neurons were present in [i]Tyro3[/i]-transgenic [i]anx/anx[/i] mice at P19. Although no differences in R7W-Tyro3 signal sequence function or protein localization were discernible [i]in vitro[/i], 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 [i]in vivo[/i] Further analyses revealed that the C19T [i]Tyro3[/i] mutation is present in a few other mouse strains, and hence is not the causative [i]anx[/i] mutation, but rather an [i]anx[/i] 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.
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