Neuron
Volume 92, Issue 2, 19 October 2016, Pages 392-406
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Article
Molecular and Neural Functions of Rai1, the Causal Gene for Smith-Magenis Syndrome

https://doi.org/10.1016/j.neuron.2016.09.019Get rights and content
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Highlights

  • Rai1 preferentially binds active promoters and promotes transcription

  • Pan-neural loss of Rai1 causes motor function and learning deficits and obesity

  • Rai1 loss in inhibitory and subcortical excitatory neurons causes learning deficits

  • Rai1 loss in subcortical excitatory, Sim1+, and SF1+ neurons causes obesity

Summary

Haploinsufficiency of Retinoic Acid Induced 1 (RAI1) causes Smith-Magenis syndrome (SMS), which is associated with diverse neurodevelopmental and behavioral symptoms as well as obesity. RAI1 encodes a nuclear protein but little is known about its molecular function or the cell types responsible for SMS symptoms. Using genetically engineered mice, we found that Rai1 preferentially occupies DNA regions near active promoters and promotes the expression of a group of genes involved in circuit assembly and neuronal communication. Behavioral analyses demonstrated that pan-neural loss of Rai1 causes deficits in motor function, learning, and food intake. These SMS-like phenotypes are produced by loss of Rai1 function in distinct neuronal types: Rai1 loss in inhibitory neurons or subcortical glutamatergic neurons causes learning deficits, while Rai1 loss in Sim1+ or SF1+ cells causes obesity. By integrating molecular and organismal analyses, our study suggests potential therapeutic avenues for a complex neurodevelopmental disorder.

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