How much is too much? Phenotypic consequences of Rai1 overexpression in mice

Abstract

The retinoic acid induced 1 (RAI1) gene when deleted or mutated results in Smith-Magenis syndrome (SMS), while duplication of 17p11.2, including RAI1, results in the dup(17)(p11.2) syndrome characterized by mental retardation, growth and developmental delays, and hyperactivity. Mouse models for these human syndromes may help define critical roles for RAI1 in mammalian development and homeostasis that otherwise cannot be deduced from patient studies. A mouse model for duplication, Dp(11)17 þ , involving Rai1 has been reported. However, this mutant was engineered on a mixed genetic background confounding phenotypic effects due to possible modifier genes. We have therefore created and evaluated mice with a graded series of four (hemizygous) and six (homozygous) copies of Rai1, and overexpressing Rai1 41.5-fold and 42-fold, respectively. Data show that Rai1-transgenic mice have growth retardation, increased locomotor activity, and abnormal anxiety-related behavior compared to wild-type littermates. Rai1-transgenic mice also have an altered gait with short strides and long sways, impaired ability on a cagetop hang test, decreased forelimb grip strength, and a dominant social behavior. Further, analyses of homozygous transgenic mice revealed a dosage-dependent exacerbation of the phenotype, including extreme growth retardation, severe neurological deficits, and increased hyperactivity. Our results show that Rai1 dosage has major consequences on molecular processes involved in growth, development, and neurological and behavioral functions, thus providing evidence for several dosage-thresholds for phenotypic manifestations causing dup(17)(p11.2) syndrome or SMS in humans.

Genetic architecture of reciprocal CNVs

“…These phenotypes are also observed in dup patients with Potocki-Lupski syndrome. Further, increased anxiety and hyperactivity, growth retardation, and altered motor and sensory coordination, were observed in Rai1 -overexpressant mice, recapitulating phenotypes observed in patients with 17p11.2 duplication 81 . These data suggest that over- and under-expression of RAI1 cause similar phenotypes that are pathognomonic of the two syndromes.…”

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

“…Rai1 heterozygous mice display mild SMS-like symptoms including obesity, circadian abnormalities, and characteristic craniofacial features (Bi et al, 2005; Lacaria et al, 2013). Overexpression of Rai1 in mice results in growth retardation, hyperactivity, and motor deficits (Girirajan et al, 2008). Given the broad expression pattern of Rai1 and diverse SMS symptoms, it is critical to determine whether specific symptoms are results of Rai1 requirement in specific cell types, in order to understand SMS pathogenesis and develop targeted therapies.…”

Dietary Regimens Modify Early Onset of Obesity in Mice Haploinsufficient for Rai1

“…Truncal-abdominal obesity is observed in a majority of SMS patients during early adolescence and other SMS mouse models have shown obesity phenotypes, further implicating RAI1 as a contributor to obesity and body weight [7]–[9], [11], [23], [24]. Furthermore, there is a well-established body of evidence implicating chromatin-modifying proteins in the development of obesity.…”