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

Abstract：

: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.

journal_name

Nat Neurosci

journal_title

Nature neuroscience

authors

Hess ME,Hess S,Meyer KD,Verhagen LA,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

doi

10.1038/nn.3449

subject

Has Abstract

pub_date

2013-08-01 00:00:00

pages

1042-8

issue

8

eissn

1097-6256

issn

1546-1726

pii

nn.3449

journal_volume

16

pub_type

杂志文章

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