The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry.

Published

Journal Article

Dopaminergic (DA) signaling governs the control of complex behaviors, and its deregulation has been implicated in a wide range of diseases. Here we demonstrate that inactivation of the Fto gene, encoding a nucleic acid demethylase, impairs dopamine receptor type 2 (D2R) and type 3 (D3R) (collectively, 'D2-like receptor')-dependent control of neuronal activity and behavioral responses. Conventional and DA neuron-specific Fto knockout mice show attenuated activation of G protein-coupled inwardly-rectifying potassium (GIRK) channel conductance by cocaine and quinpirole. Impaired D2-like receptor-mediated autoinhibition results in attenuated quinpirole-mediated reduction of locomotion and an enhanced sensitivity to the locomotor- and reward-stimulatory actions of cocaine. Analysis of global N(6)-methyladenosine (m(6)A) modification of mRNAs using methylated RNA immunoprecipitation coupled with next-generation sequencing in the midbrain and striatum of Fto-deficient mice revealed increased adenosine methylation in a subset of mRNAs important for neuronal signaling, including many in the DA signaling pathway. Several proteins encoded by these mRNAs had altered expression levels. Collectively, FTO regulates the demethylation of specific mRNAs in vivo, and this activity relates to the control of DA transmission.

Full Text

Duke Authors

Cited Authors

  • Hess, ME; Hess, S; Meyer, KD; Verhagen, LAW; Koch, L; Brönneke, HS; Dietrich, MO; Jordan, SD; Saletore, Y; Elemento, O; Belgardt, BF; Franz, T; Horvath, TL; Rüther, U; Jaffrey, SR; Kloppenburg, P; Brüning, JC

Published Date

  • August 2013

Published In

Volume / Issue

  • 16 / 8

Start / End Page

  • 1042 - 1048

PubMed ID

  • 23817550

Pubmed Central ID

  • 23817550

Electronic International Standard Serial Number (EISSN)

  • 1546-1726

Digital Object Identifier (DOI)

  • 10.1038/nn.3449

Language

  • eng

Conference Location

  • United States