Molecular and Neural Functions of Rai1 , the Causal Gene for Smith-Magenis Syndrome
| Autor: | Lindsay A. Schwarz, Howard Y. Chang, Jin Xu, Tiffany Nguyen, Alex W. Wilkinson, Casey J. Guenthner, Or Gozani, Liqun Luo, Mehrdad Shamloo, Wei-Hsiang Huang |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cell type DNA Copy Number Variations Retinoic acid induced 1 Glutamic Acid Haploinsufficiency Biology Article Eating Mice 03 medical and health sciences Glutamatergic Neurodevelopmental disorder Basic Helix-Loop-Helix Transcription Factors medicine Animals Learning Gene Knock-In Techniques Obesity Nuclear protein Mice Knockout Neurons Genetics Behavior Animal General Neuroscience Neural Inhibition Smith–Magenis syndrome medicine.disease Repressor Proteins Phenotype 030104 developmental biology Gene Expression Regulation Trans-Activators SIM1 RNA Splicing Factors Smith-Magenis Syndrome Neuroscience |
| Zdroj: | Neuron. 92:392-406 |
| ISSN: | 0896-6273 |
| DOI: | 10.1016/j.neuron.2016.09.019 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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