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

Abstract

SUMMARY 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.

Rai1 frees mice from the repression of active wake behaviors by light

“…Rai1 is widely expressed throughout the brain with high levels of expression observed in the olfactory bulb, cerebral cortex, hippocampus, striatum, thalamus, hypothalamus, cerebellum, and brainstem (Toulouse et al, 2003; Bi et al, 2007; Fragoso et al, 2015; Huang et al, 2016). Because circadian and/or light-dependent changes in Rai1 expression in the brain may contribute to the phenotypes we observed in Rai1 -haploinsufficient mice, we sampled brain tissue under LD12:12 conditions at 3-hr intervals in wild-type mice.…”

“…at light onset under entrained conditions) might have contributed to the earlier preferred activity onset in Rai1 +/- mice and also to the compression of alpha under entrained, LD12:12 conditions (compared to DD). Alpha compression during re-entrainment is accompanied by memory impairments (Ruby et al, 2015) and, assuming that in Rai1 +/- mice alpha is being compressed by 2.5 hr on a daily basis under LD12:12 conditions, might also have contributed to cognitive deficits reported for Rai1- compromised mice kept under these same lighting conditions (Bi et al, 2007; Huang et al, 2016). It is therefore of interest to verify whether memory deficits persist under LD regimens with shorter than 12 hr photoperiods better matching the longer endogenous active period observed in Rai1 +/- mice.…”

“…RAI1 is a highly conserved transcriptional regulator (Carmona-Mora et al, 2010) with high neuronal expression (Toulouse et al, 2003; Fragoso et al, 2015), and recent evidence shows that it acts as a positive transcriptional regulator by binding to active promotor and enhancer regions (Huang et al, 2016). Among RAI1 target genes are Bdnf ( brain-derived neurotrophic factor ) and Htr2c ( serotonin receptor 2c ) (Huang et al, 2016; Burns et al, 2010), both of which are implicated in hyperphagia leading to obesity, a phenotype accompanying SMS, concomitant with altered locomotor activity (Huang et al, 2016; Burns et al, 2010; Kernie et al, 2000; Nonogaki et al, 2003). Moreover, as its name indicates, Rai1 expression is induced by retinoic acid (Imai et al, 1995).…”

“…Moreover, as its name indicates, Rai1 expression is induced by retinoic acid (Imai et al, 1995). Because retinoic acid signaling is a major pathway involved in eye formation (Cvekl and Wang, 2009) and other developmental processes, and because RAI1 appears to help assemble and maintain neuronal circuitry (Huang et al, 2016), the lack of one Rai1 allele is likely to impact eye development and light signaling pathways, maybe through its target gene Bdnf , which is known to be important for retinal development and synaptic connectivity (Grishanin et al, 2008). While we found no apparent structural differences in the retina, the ERG results did reveal a profound attenuation of the response to light pointing to altered retinal function.…”

Developmental disorders with intellectual disability driven by chromatin dysregulation: Clinical overlaps and molecular mechanisms

“…A summary of both distinctive and common clinical traits are shown in the Venn diagram in Figure . RAI1 is a transcriptional modulator involved in cell growth/cell cycle regulation, bone and skeletal development, lipid and glucose metabolisms, embryonic development and neuronal differentiation, behavioral functions and circadian activity. RAI1 works as chromatin reader acting preferentially at active promoters and enhancers of several genes .…”