Comparative analyses of the Smith−Magenis syndrome protein RAI1 in mice and common marmoset monkeys

Abstract

Retinoic acid‐induced 1 (RAI1) encodes a transcriptional regulator critical for brain development and function. RAI1 haploinsufficiency in humans causes a syndromic autism spectrum disorder known as Smith−Magenis syndrome (SMS). The neuroanatomical distribution of RAI1 has not been quantitatively analyzed during the development of the prefrontal cortex, a brain region critical for cognitive function and social behaviors and commonly implicated in autism spectrum disorders, including SMS. Here, we performed comparative analyses to uncover the evolutionarily convergent and divergent expression profiles of RAI1 in major cell types during prefrontal cortex maturation in common marmoset monkeys (Callithrix jacchus) and mice (Mus musculus). We found that while RAI1 in both species is enriched in neurons, the percentage of excitatory neurons that express RAI1 is higher in newborn mice than in newborn marmosets. By contrast, RAI1 shows similar neural distribution in adult marmosets and adult mice. In marmosets, RAI1 is expressed in several primate‐specific cell types, including intralaminar astrocytes and MEIS2‐expressing prefrontal GABAergic neurons. At the molecular level, we discovered that RAI1 forms a protein complex with transcription factor 20 (TCF20), PHD finger protein 14 (PHF14), and high mobility group 20A (HMG20A) in the marmoset brain. In vitro assays in human cells revealed that TCF20 regulates RAI1 protein abundance. This work demonstrates that RAI1 expression and protein interactions are largely conserved but with some unique expression in primate‐specific cells. The results also suggest that altered RAI1 abundance could contribute to disease features in disorders caused by TCF20 dosage imbalance.

Allele-Specific Regulation of the Candidate Autism Liability Gene RAI1 by the Enhancer Variant rs4925102 (C/G)

“…Retinoic acid-induced 1 (RAI1) is a dosage-sensitive gene, for which a 50% change in expression levels due to deletion/mutation or duplication of a single copy causes Smith-Magenis syndrome (SMS) [1][2][3] or Potocki-Lupski syndrome (PTLS) [4], respectively. The occurrence of autistic phenotypes in clinical cases with SMS and PTLS has been reported to be over 60% (PTLS) [5] to over 90% (SMS) [6].…”