Molecular and Neural Functions of Rai1, the Causal Gene for Smith-Magenis Syndrome.
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.
Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: weihsiah@stanford.edu.
Wei-Hsiang
WH
Huang
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.
Casey J
CJ
Guenthner
Center for Personal Dynamic Regulomes and Program in Epithelial Biology, Stanford University, Stanford, CA 94305, USA.
Jin
J
Xu
Stanford Behavioral and Functional Neuroscience Laboratory, Stanford University, Stanford, CA 94305, USA.
Tiffany
T
Nguyen
Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA.
Lindsay A
LA
Schwarz
Department of Biology, Stanford University, Stanford, CA 94305, USA.
Alex W
AW
Wilkinson
Department of Biology, Stanford University, Stanford, CA 94305, USA.
Or
O
Gozani
Center for Personal Dynamic Regulomes and Program in Epithelial Biology, Stanford University, Stanford, CA 94305, USA.
Howard Y
HY
Chang
Stanford Behavioral and Functional Neuroscience Laboratory, Stanford University, Stanford, CA 94305, USA; Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA.
Mehrdad
M
Shamloo
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.
Liqun
L
Luo
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001522:Behavior, Animal; D056915:DNA Copy Number Variations; D004435:Eating / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D055879:Gene Knock-In Techniques; D018698:Glutamic Acid / Q000378:metabolism; D057895:Haploinsufficiency; D007858:Learning; D051379:Mice; D018345:Mice, Knockout; D009433:Neural Inhibition; D009474:Neurons / Q000378:metabolism*; D009765:Obesity / Q000235:genetics*; D010641:Phenotype; D000072260:RNA Splicing Factors / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D058496:Smith-Magenis Syndrome / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*
D051792:Basic Helix-Loop-Helix Proteins; D018698:Glutamic Acid; D000072260:RNA Splicing Factors; D012097:Repressor Proteins; D015534:Trans-Activators; C502844:Rai1 protein, mouse; C491514:Sf1 protein, mouse; C101750:Sim1 protein, mouse
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