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

Wei-Hsiang Huang; Casey J Guenthner; Jin Xu; Tiffany Nguyen; Lindsay A Schwarz; Alex W Wilkinson; Or Gozani; Howard Y Chang; Mehrdad Shamloo; Liqun Luo

doi:10.1016/j.neuron.2016.09.019

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

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

Authors

Affiliations

¹ Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: [email protected].
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: [email protected].

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.

MeSH terms

Animals
Basic Helix-Loop-Helix Transcription Factors / metabolism
Behavior, Animal*
DNA Copy Number Variations
Eating / genetics
Gene Expression Regulation / genetics*
Gene Knock-In Techniques
Glutamic Acid / metabolism
Haploinsufficiency
Learning
Mice
Mice, Knockout
Neural Inhibition
Neurons / metabolism*
Obesity / genetics*
Phenotype
RNA Splicing Factors / metabolism
Repressor Proteins / metabolism
Smith-Magenis Syndrome / genetics*
Trans-Activators / genetics*

Substances

Basic Helix-Loop-Helix Transcription Factors
RNA Splicing Factors
Rai1 protein, mouse
Repressor Proteins
Sf1 protein, mouse
Sim1 protein, mouse
Trans-Activators
Glutamic Acid

Abstract

MeSH terms

Substances

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