PTEN (phosphatase and tensin homolog) encodes a lipid phosphatase that negatively regulates the PI3K signaling pathway. Its primary role is to counteract PI3K kinase activity and thus inhibit the activation of AKT. PTEN, widely recognized as a tumor suppressor, has been extensively studied in tumor biology, as loss of PTEN function is the second most common type of mutation (next to P53) found in human cancers. New studies, however, show that PTEN also plays a role in neurological disorders, such as Parkinson Disease, epilepsy, and Autism Spectrum Disorders (ASD). The PTEN-regulated PI3K/AKT signal transduction pathway crosstalks with several other important signaling pathways, including Wnt/GSK3, which is linked to Schizophrenia (SZ) and bipolar disorder (BD). While these functional aspects of PTEN have been extensively studied in the context of its lipid phosphatase activity on PI3K, PTEN can also inhibit cell growth through its protein phosphatase activity. More recently, it was discovered that PTEN has a third function that is totally independent from its encoded protein;PTEN mRNA forms a competing interaction with other RNAs due to shared miRNA targets sites, with the most notable case being PTENP1, a pseudogene derived from PTEN. Motivated by this new intriguing finding and our long-standing interest in pseudogene function and the genetic basis of ASD/BD/SZ, we propose to investigate the role of this PTEN/PTENP1 interaction in early neurogenesis and to identify the miRNA regulatory network behind this interaction using a systems genomic approach and induced pluripotent stem cell (iPSC) technology for in vitro modeling of neurodevelopment. We hypothesize that mutations or polymorphisms affecting PTENP1 expression or interfering with the PTEN-miRNA-PTENP1 interaction will perturb this competing RNA network system and thus could represent new risk factors for ASD, SZ and other neurodevelopmental disorders. Our findings will be important for understanding the role of non-coding RNAs and pseudogenes in neuropsychiatric disorders, both of which may help explain disease-associated SNPs and CNVs in non-coding regions of the human genome.

Public Health Relevance

This project will investigate the interacting roles of human gene PTEN and its deriving pseudogene PTENP1 in early neurogenesis and their implications in neurodevelopmental disorders using a systems genomics approach.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH099452-02
Application #
8547842
Study Section
Special Emphasis Panel (ZRG1-ETTN-H (09))
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2012-09-19
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$240,480
Indirect Cost
$96,480
Name
Albert Einstein College of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Nebel, Rebecca A; Zhao, Dejian; Pedrosa, Erika et al. (2016) Reduced CYFIP1 in Human Neural Progenitors Results in Dysregulation of Schizophrenia and Epilepsy Gene Networks. PLoS One 11:e0148039
Lin, Mingyan; Lachman, Herbert M; Zheng, Deyou (2016) Transcriptomics analysis of iPSC-derived neurons and modeling of neuropsychiatric disorders. Mol Cell Neurosci 73:32-42
Zhao, Dejian; Lin, Mingyan; Chen, Jian et al. (2015) MicroRNA Profiling of Neurons Generated Using Induced Pluripotent Stem Cells Derived from Patients with Schizophrenia and Schizoaffective Disorder, and 22q11.2 Del. PLoS One 10:e0132387
Wang, Ping; Lin, Mingyan; Pedrosa, Erika et al. (2015) CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in neurodevelopment. Mol Autism 6:55
Adam, Rene C; Yang, Hanseul; Rockowitz, Shira et al. (2015) Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice. Nature 521:366-70
Sun, Jian; Rockowitz, Shira; Chauss, Daniel et al. (2015) Chromatin features, RNA polymerase II and the comparative expression of lens genes encoding crystallins, transcription factors, and autophagy mediators. Mol Vis 21:955-73
Rockowitz, Shira; Zheng, Deyou (2015) Significant expansion of the REST/NRSF cistrome in human versus mouse embryonic stem cells: potential implications for neural development. Nucleic Acids Res 43:5730-43
Sun, Jian; Rockowitz, Shira; Xie, Qing et al. (2015) Identification of in vivo DNA-binding mechanisms of Pax6 and reconstruction of Pax6-dependent gene regulatory networks during forebrain and lens development. Nucleic Acids Res 43:6827-46
Guo, Xingyi; Lin, Mingyan; Rockowitz, Shira et al. (2014) Characterization of human pseudogene-derived non-coding RNAs for functional potential. PLoS One 9:e93972
Rockowitz, Shira; Lien, Wen-Hui; Pedrosa, Erika et al. (2014) Comparison of REST cistromes across human cell types reveals common and context-specific functions. PLoS Comput Biol 10:e1003671

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