Bi, W. et al. Rai1 deficiency in mice causes learning impairment and motor dysfunction, whereas Rai1 heterozygous mice display minimal behavioral phenotypes. Hum. Mol. Genet. 16, 1802-1813

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030-3498, USA.
Human Molecular Genetics (Impact Factor: 6.39). 09/2007; 16(15):1802-13. DOI: 10.1093/hmg/ddm128
Source: PubMed


Smith-Magenis syndrome (SMS) is associated with an approximately 3.7 Mb common deletion in 17p11.2 and characterized by its craniofacial and neurobehavioral abnormalities. The reciprocal duplication leads to dup(17)(p11.2p11.2) associated with the Potocki-Lupski syndrome (PLS), a neurological disorder whose features include autism. Retinoic acid induced 1 (RAI1) appears to be responsible for the majority of clinical features in both SMS and PLS. Mouse models of these syndromes harboring an approximately 2 Mb chromosome engineered deletion and duplication, respectively, displayed abnormal locomotor activity and/or learning deficits. To determine the contribution of RAI1 in the neurobehavioral traits in SMS, we performed a battery of behavioral tests on Rai1 mutant mice and the Df(11)17-1/+ mice that have a small deletion of approximately 590 kb. The mice with the small deletion were hypoactive like the large deletion mice and they also showed learning deficits. The Rai1+/- mice exhibited normal locomotor activity. However, they had an abnormal electroencephalogram with overt seizure observed in a subset of mice. The few surviving Rai1-/- mice displayed more severe neurobehavioral abnormalities including hind limb clasping, overt seizures, motor impairment and context- and tone-dependant learning deficits. X-gal staining of the Rai1+/- mice suggests that Rai1 is predominantly expressed in neurons of the hippocampus and the cerebellum. Our results suggest that Rai1 is a critical gene in the central nervous system functioning in a dosage sensitive manner and that the neurobehavioral phenotype is modified by regulator(s) in the approximately 590 kb genomic interval, wherein the major modifier affecting the craniofacial penetrance resides.

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Available from: Weimin Bi, Dec 23, 2013
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    • "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. "
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    ABSTRACT: Smith-Magenis syndrome is a complex genomic disorder in which a majority of individuals are obese by adolescence. While an interstitial deletion of chromosome 17p11.2 is the leading cause, mutation or deletion of the RAI1 gene alone results in most features of the disorder. Previous studies have shown that heterozygous knockout of Rai1 results in an obese phenotype in mice and that Smith-Magenis syndrome mouse models have a significantly reduced fecundity and an altered transmission pattern of the mutant Rai1 allele, complicating large, extended studies in these models. In this study, we show that breeding C57Bl/6J Rai1+/- mice with FVB/NJ to create F1 Rai1+/- offspring in a mixed genetic background ameliorates both fecundity and Rai1 allele transmission phenotypes. These findings suggest that the mixed background provides a more robust platform for breeding and larger phenotypic studies. We also characterized the effect of dietary intake on Rai1+/- mouse growth during adolescent and early adulthood developmental stages. Animals fed a high carbohydrate or a high fat diet gained weight at a significantly faster rate than their wild type littermates. Both high fat and high carbohydrate fed Rai1+/- mice also had an increase in body fat and altered fat distribution patterns. Interestingly, Rai1+/- mice fed different diets did not display altered fasting blood glucose levels. These results suggest that dietary regimens are extremely important for individuals with Smith- Magenis syndrome and that food high in fat and carbohydrates may exacerbate obesity outcomes.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "A reciprocal duplication of this genomic region on chromosome 17 is correlated with another ASD neuropsychiatric disorder, the Potocki-Lupski syndrome (PLS). Both SMS and PLS map to dysfunctions in the Retinoic acid-induced 1 (RAI1) gene which functions through the RXR complex [15]. "
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    ABSTRACT: Autism spectrum disorders (ASDs) have become increasingly common in recent years. The discovery of single-nucleotide polymorphisms and accompanying copy number variations within the genome has increased our understanding of the architecture of the disease. These genetic and genomic alterations coupled with epigenetic phenomena have pointed to a neuroimmunopathological mechanism for ASD. Model animal studies, developmental biology, and affective neuroscience laid a foundation for dissecting the neural pathways impacted by these disease-generating mechanisms. The goal of current autism research is directed toward a systems biological approach to find the most basic genetic and environmental causes to this severe developmental disease. It is hoped that future genomic and neuroimmunological research will be directed toward finding the road toward prevention, treatment, and cure of ASD.
    Full-text · Article · May 2011
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    • "The limb clasping test consists in analyzing the response of the mouse limbs when the mice are held suspended in the air by the tail. The wild type mice open their limbs widely [46], [47]. "
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    ABSTRACT: Rnd proteins are a subfamily of Rho GTPases involved in the control of actin cytoskeleton dynamics and other cell functions such as motility, proliferation and survival. Unlike other members of the Rho family, Rnd proteins lack GTPase activity and therefore remain constitutively active. We have recently described that RhoE/Rnd3 is expressed in the Central Nervous System and that it has a role in promoting neurite formation. Despite their possible relevance during development, the role of Rnd proteins in vivo is not known. To get insight into the in vivo function of RhoE we have generated mice lacking RhoE expression by an exon trapping cassette. RhoE null mice (RhoE gt/gt) are smaller at birth, display growth retardation and early postnatal death since only half of RhoE gt/gt mice survive beyond postnatal day (PD) 15 and 100% are dead by PD 29. RhoE gt/gt mice show an abnormal body position with profound motor impairment and impaired performance in most neurobehavioral tests. Null mutant mice are hypoactive, show an immature locomotor pattern and display a significant delay in the appearance of the hindlimb mature responses. Moreover, they perform worse than the control littermates in the wire suspension, vertical climbing and clinging, righting reflex and negative geotaxis tests. Also, RhoE ablation results in a delay of neuromuscular maturation and in a reduction in the number of spinal motor neurons. Finally, RhoE gt/gt mice lack the common peroneal nerve and, consequently, show a complete atrophy of the target muscles. This is the first model to study the in vivo functions of a member of the Rnd subfamily of proteins, revealing the important role of Rnd3/RhoE in the normal development and suggesting the possible involvement of this protein in neurological disorders.
    Full-text · Article · Apr 2011 · PLoS ONE
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