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.


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*


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