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Neuron. 2016 Oct 19;92(2):392-406. doi: 10.1016/j.neuron.2016.09.019. Epub 2016 Sep 29.

Molecular and Neural Functions of Rai1, the Causal Gene for Smith-Magenis Syndrome.

Author information

1
Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: weihsiah@stanford.edu.
2
Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA; Neurosciences Program, Stanford University, Stanford, CA 94305, USA.
3
Center for Personal Dynamic Regulomes and Program in Epithelial Biology, Stanford University, Stanford, CA 94305, USA.
4
Stanford Behavioral and Functional Neuroscience Laboratory, Stanford University, Stanford, CA 94305, USA.
5
Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA.
6
Department of Biology, Stanford University, Stanford, CA 94305, USA.
7
Stanford Behavioral and Functional Neuroscience Laboratory, Stanford University, Stanford, CA 94305, USA; Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA.
8
Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA; Neurosciences Program, Stanford University, Stanford, CA 94305, USA. Electronic address: lluo@stanford.edu.

Abstract

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.

PMID:
27693255
PMCID:
PMC5098476
DOI:
10.1016/j.neuron.2016.09.019
[Indexed for MEDLINE]
Free PMC Article

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