The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model

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.

Retracted: MicroRNA‐219 decreases hippocampal long‐term potentiation inhibition and hippocampal neuronal cell apoptosis in type 2 diabetes mellitus mice by suppressing the NMDAR signaling pathway

“…MiRs are known to have the ability to regulate inflammation, synaptic strength, ion channels, neuronal and glial function, and apoptosis . MicroRNA‐219 (miR‐219) is a brain‐specific microRNA, and its dysregulation has been previously observed in neurodevelopmental disorders, such as schizophrenia . It is encoded in microRNAs and abundantly expressed in fetal hippocampus, which can regulate the aging of brain, and alter in specific microRNA complexity occurrence in Alzheimer hippocampus .…”

Melatonin Enhances Proliferation and Modulates Differentiation of Neural Stem Cells Via Autophagy in Hyperglycemia

“…Several studies on offspring of mothers with GDM show higher rates of gross and fine motor abnormalities , attention deficit hyperactivity disorder , learning difficulties , and autism spectrum disorder . Neurodevelopment disorders or neural congenital malformations have been found to be due to an imbalance between proliferation and differentiation of neural stem cells (NSCs).…”

Screening the expression of several miRNAs from TaqMan Low Density Array in traumatic brain injury: miR‐219a‐5p regulates neuronal apoptosis by modulating CCNA2 and CACUL1

“…miR‐219, a known brain‐specific miRNA, is dysregulated in neurodevelopmental diseases, including schizophrenia, meningioma bipolar disorder and depression (Zucchi et al ; Zhi et al ). A recent study suggested that overexpression of miR‐219 in neural stem cells robustly inhibits cell proliferation and induces neuronal differentiation (Murai et al ). Another recent report also described that miR‐219 appears to decrease progenitor cell sensitivity to Shh signaling, thereby driving neural progenitors towards differentiation (Hudish et al ).…”