The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model
Year: 2016
Type: article
Abstract: Dysregulated expression of miR-219, a brain-specific microRNA, has been observed in neurodevelopmental disorders, such as schizophrenia (SCZ). However, its role in normal mammalian neural stem cells (NSCs) and in SCZ pathogenesis remains unknown. We show here that the nuclear receptor TLX, an essential regulator of NSC proliferation and self-renewal, inhibits miR-219 processing. miR-219 suppresses mouse NSC proliferation downstream of TLX. Moreover, we demonstrate upregulation of miR-219 and downregulation of TLX expression in NSCs derived from SCZ patient iPSCs and DISC1-mutant isogenic iPSCs. SCZ NSCs exhibit reduced cell proliferation. Overexpression of TLX or inhibition of miR-219 action rescues the proliferative defect in SCZ NSCs. Therefore, this study uncovers an important role for TLX and miR-219 in both normal neurodevelopment and in SCZ patient iPSC-derived NSCs. Moreover, this study reveals an unexpected role for TLX in regulating microRNA processing, independent of its well-characterized role in transcriptional regulation.
Source: Nature Communications
DOI: 10.1038/ncomms10965
Language: English
Subfield: Developmental Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: California Institute for Regenerative Medicine, National Alliance for Research on Schizophrenia and Depression, Maryland Stem Cell Research Fund, National Institutes of Health, California State University Long Beach, National Institute of Mental Health, National Cancer Institute, National Institute of Neurological Disorders and Stroke
Awards: G1132761873, G1721452835, Modeling Alexander disease using patient-specific induced pluripotent stem cells, CIRM Stem Cell Research Biotechnology Training Program at CSULB, Calcium signaling in neuronal navigation, G4640031714, G532196934, Developing a therapeutic candidate for Canavan disease using induced pluripotent stem cell, G7629857367, Circuitry mechanisms underlying normal and aberrant adult hippocampal neurogenesis, G8734015584, Cancer Center Support Grant
OpenAlex ID: W2293879246