The Fragile X Syndrome is caused by transcriptional silencing of FMR1, the gene encoding the RNA binding protein FMRP. FMRP represses mRNA translation in the brain at the level of ribosome transit (polypeptide elongation). We have shown that Fragile X resuce occurs when FMRP knockout (KG) mice are subjected to genetic albation of the transational activator proiten CPEB, the signaling molecule p70S6 kinase 1 (S6K), or inhibiton of PI3 Kinase (PI3K). Moreover, protein synthesis levels, which are aberrantly high in the absence of FMRP, return to normal when CPEB, S6K1, or PI3K are ablated or inhibited. The RNAseq/bioinformatics (RB) core will provide computational analysis of newly developed genome-wide methods to investigate translational control and cytoplasmic polyadenylation in genetically-altered mice. The RB core will also serve as a data hub and standardize analysis for the three projects, and will provide an interface to sequencing facilities for the generation of cDNA libraries and deep sequencing. The RB core will assist the three research projects in data analysis and interpretation. The RB core has devised new computational methods to examine translation homeostasis in disease model mice and in human Fragile X iPS cells.
The Fragile X Syndrome is the most common inherited for intellectual disability and the most prevalent monogenic form of autism. This RNAseq/bioinformatics core is a key part of this Center as it seeks to understand how translational homeostasis regulates the Fragile X syndrome. The Core will provide assistant, insight, and computational analysis assessing Fragile X model mice and human Fragile X IPS cells
|Richter, Joel D; Bassell, Gary J; Klann, Eric (2015) Dysregulation and restoration of translational homeostasis in fragile X syndrome. Nat Rev Neurosci 16:595-605|
|Richter, Joel D; Coller, Jeff (2015) Pausing on Polyribosomes: Make Way for Elongation in Translational Control. Cell 163:292-300|
|Huynh, Thu N; Shah, Manan; Koo, So Yeon et al. (2015) eIF4E/Fmr1 double mutant mice display cognitive impairment in addition to ASD-like behaviors. Neurobiol Dis 83:67-74|
|Gross, Christina; Hoffmann, Anne; Bassell, Gary J et al. (2015) Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back. Neurotherapeutics 12:584-608|