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Divergent Dysregulation of Gene Expression in Murine Models of Fragile X Syndrome and Tuberous Sclerosis

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Divergent Dysregulation of Gene Expression in Murine Models of Fragile X Syndrome and Tuberous Sclerosis Divergent dysregulation of gene expression in murine models of fragile X syndrome and tuberous sclerosis The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Kong, Sek, Mustafa Sahin, Christin D Collins, Mary H Wertz, Malcolm G Campbell, Jarrett D Leech, Dilja Krueger, Mark F Bear, Louis M Kunkel, and Isaac S Kohane. “Divergent Dysregulation of Gene Expression in Murine Models of Fragile X Syndrome and Tuberous Sclerosis.” Mol Autism 5, no. 1 (2014): 16. As Published http://dx.doi.org/10.1186/2040-2392-5-16 Publisher Biomed Central Ltd. Version Final published version Citable link http://hdl.handle.net/1721.1/102332 Terms of Use Creative Commons Attribution Detailed Terms http://creativecommons.org/licenses/by/2.0/ Kong et al. Molecular Autism 2014, 5:16 http://www.molecularautism.com/content/5/1/16 RESEARCH Open Access Divergent dysregulation of gene expression in murine models of fragile X syndrome and tuberous sclerosis Sek Won Kong1,5†, Mustafa Sahin2†, Christin D Collins3, Mary H Wertz2, Malcolm G Campbell5, Jarrett D Leech2, Dilja Krueger4, Mark F Bear4, Louis M Kunkel3 and Isaac S Kohane1,5* Abstract Background: Fragile X syndrome and tuberous sclerosis are genetic syndromes that both have a high rate of comorbidity with autism spectrum disorder (ASD). Several lines of evidence suggest that these two monogenic disorders may converge at a molecular level through the dysfunction of activity-dependent synaptic plasticity. Methods: To explore the characteristics of transcriptomic changes in these monogenic disorders, we profiled genome-wide gene expression levels in cerebellum and blood from murine models of fragile X syndrome and tuberous sclerosis. Results: Differentially expressed genes and enriched pathways were distinct for the two murine models examined, with the exception of immune response-related pathways. In the cerebellum of the Fmr1 knockout (Fmr1-KO) model, the neuroactive ligand receptor interaction pathway and gene sets associated with synaptic plasticity such as long-term potentiation, gap junction, and axon guidance were the most significantly perturbed pathways. The phosphatidylinositol signaling pathway was significantly dysregulated in both cerebellum and blood of Fmr1-KO mice. In Tsc2 heterozygous (+/−) mice, immune system-related pathways, genes encoding ribosomal proteins, and glycolipid metabolism pathways were significantly changed in both tissues. Conclusions: Our data suggest that distinct molecular pathways may be involved in ASD with known but different genetic causes and that blood gene expression profiles of Fmr1-KO and Tsc2+/− mice mirror some, but not all, of the perturbed molecular pathways in the brain. Keywords: Fragile X syndrome, Tuberous sclerosis, Autism, Cerebellum, Blood, Gene expression, Murine model Background etiologies implicated in ASD may converge on a few com- Autism spectrum disorder (ASD) manifests significant mon pathways. Further research on single gene disorders heterogeneity in part because of the interaction of under- associated with ASD such as tuberous sclerosis complex lying genetic [1-3], neurobiological, and environmental (TSC) and fragile X syndrome (FXS) may lead to an un- factors [4,5] during early brain development. This hetero- derstanding of common dysfunction at the cellular or cir- geneity presents one of the main obstacles to the develop- cuit level for a majority of ASD. In a recent survey of over ment of effective treatments for ASD. The complex 14,000 individuals under age 35 with ASD in a Boston genetics of ASD suggest that it is a large set of related area hospital, Kohane and colleagues reported that the disorders with diverse mechanisms; however, many of the prevalence of genetic disorders of FXS and TSC in indi- viduals with ASD were 0.5% and 0.8% [6]. Conversely, 30% and 50-61% of patients with FXS and TSC present * Correspondence: [email protected] † ASD core symptoms, respectively [7,8]. If such shared Equal contributors pathophysiology exists, then treatments developed for a 1Informatics Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA target in one disorder might be applicable to others. Mouse 5Center for Biomedical Informatics, Harvard Medical School, Boston, MA, USA models for ASD serve an increasingly important role in Full list of author information is available at the end of the article © 2014 Kong et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. Kong et al. Molecular Autism 2014, 5:16 Page 2 of 11 http://www.molecularautism.com/content/5/1/16 providing a pre-clinical test of promising pharmacological Methods therapeutics [9,10]. Inactivating mutation in Tsc2 (Tsc2+/− Murine models of fragile X syndrome and tuberous mice) showed defects in axon guidance [11] and cognitive sclerosis deficits such as impaired water maze performance [12], To identify molecular signatures of each mouse model and mice with Fmr1-knockout(KO)presentedimpair- of ASD, we performed gene expression profiling on cere- ments in long-term depression, hyperactivity, anxiety-like, bellum and peripheral blood collected from two mouse and unusual social behaviors [13]. Therefore, deter- models and compared to wild-type (WT) controls. We mining the degree to which there are shared molecular used cerebellum where the most consistent abnormalities mechanisms in these models will inform clinical trials, were reported in the patients with ASD [14]. Post-mortem particularly those that address populations with genetically studies have shown a reduced number of Purkinje cells heterogeneous causes of ASD. (PC), and several neuroimaging studies reported enlarged Although several cellular mechanisms may be impli- cerebella in ASD [29,30]. The cerebellum is also impli- cated (reviewed in Fatemi et al. [14]), accumulating data cated in social interaction [31], and the loss of Tsc1 from support a role for the PI3K-mTOR signaling cascade in cerebellar PC was associated with autistic-like behaviors several genetic causes of ASD. Evidence for the PI3K- [32]. Additionally, we profiled whole blood from the same mTOR pathway first emerged from TSC [15,16] and individual mouse to compare with the gene expression mutations in the PTEN gene associated with ASD and changes in cerebellum. macrocephaly [17-19]. Later, investigation of copy num- All male C57BL/6 congenic Fmr1-KO mice and ber variants (CNV) in autistic individuals identified that Tsc2+/− mice with mixed 129/SvJae-C57BL/6 J back- PI3K-mTOR pathway-related genes were located in ground have been previously described [33,34]. We pro- CNV hotspots [20]. These findings have led to the hy- filed Tsc2+/− mice since homozygous Tsc2 KO was pothesis that overactivation of the mTOR pathway could embryonic lethal. The mice were killed at 8–10 weeks lead to abnormal synaptic function owing to an excess of age following the institutional animal care and use of protein synthesis at the synapse [21]. Genetic evi- committee (IACUC) euthanasia criteria (the Boston dence that directly implicates a translation initiating Children’s Hospital IACUC animal protocol no. 12-07- factor, EIF4E, which is a downstream target of mTOR, 2227R). For the Fmr1-KO model, 5 KO and 5 WT mice in ASD has provided further support for this hypothesis were profiled, and for the Tsc2+/− model 3 transgenic and [22]. Interestingly, exposure to teratogens such as val- 3 WT mice were profiled. Paired blood and cerebellum proate in utero can lead to ASD in children [23], and samples were prepared for gene expression profiling. valproate can also modulate this signaling pathway [24], suggesting that environmental factors associated Genome-wide gene expression profiling using with ASD can also play a role in PI3K-mTOR pathway microarrays regulation [25]. More recently, studies have found that A total of 250 ng RNA was processed using established PI3K-mTOR signaling is upregulated in mouse models Affymetrix protocols for the generation of biotin-labeled of FXS, one of the most common genetic causes of cRNA, and the hybridization, staining, and scanning of ASD [26-28]. arrays were performed. Briefly, total RNA was converted Together, the aforementioned findings suggest that an to double-stranded cDNA using a T7 primer and biotin- upregulated PI3K-mTOR signaling cascade might be a labeled cRNA was then generated from the cDNA by common mechanism in ASD and therefore would po- in vitro transcription. The cRNA was quantified (using tentially be a promising drug target. Indeed, clinical A260) and fragmented. Fragmented cRNA was hybrid- trials using inhibitors of mTOR are already in progress ized to the Affymetrix Mouse Gene ST 1.0 array and in patients with TSC. We hypothesized that if the PI3K- scanned on an Affymetrix GeneChip scanner 3000 at mTOR signaling pathway is dysregulated in various 2.5 μm resolution [35]. Microarray data are available at causes of ASD, then these disorders should present with the Gene Expression Omnibus database (GSE40630). a similar gene expression profile signature. We chose to analyze TSC and FXS, two Mendelian disorders highly Validation of gene expression changes using quantitative associated with ASD. Better understanding of similarities RT-PCR and differences of the cellular and molecular defects Total RNA was extracted using TRIzol according to the leading to abnormal neurological function in these two manufacturer’s instruction. The RNA amount was mea- disorders is essential to the development of new therap- sured using the Nanodrop (Thermo Scientific); 100 ng ies for ASD. Here, we used mouse models available for of total RNA was reversed transcribed using a cDNA both genetic disorders to investigate the similarities and reverse transcription kit with random primers (Applied differences between gene expression profiles in the brain Biosystems). SyBr Green PCR Master Mix (Applied Bio- and blood cells. systems) was used to amplify and detect signals from Kong et al.
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