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The role of the nuclear receptor TLX in hippocampal neurogenesis and cognition has just begun to be explored. In this study, we generated a transgenic mouse model that expresses TLX under the control of the promoter of nestin, a neural precursor marker. Transgenic TLX expression led to mice with enlarged brains with an elongated hippocampal dentate gyrus and increased numbers of newborn neurons. Specific expression of TLX in adult hippocampal dentate gyrus via lentiviral transduction increased the numbers of BrdU(+) cells and BrdU(+)NeuN(+) neurons. Furthermore, the neural precursor-specific expression of the TLX transgene substantially rescued the neurogenic defects of TLX-null mice. Consistent with increased neurogenesis in the hippocampus, the TLX transgenic mice exhibited enhanced cognition with increased learning and memory. These results suggest a strong association between hippocampal neurogenesis and cognition, as well as significant contributions of TLX to hippocampal neurogenesis, learning, and memory.

Developing efficient models for neurological diseases enables us to uncover disease mechanisms and develop therapeutic strategies to treat them. Discovery of reprogramming somatic cells to induced pluripotent stem cells (iPSCs) has revolutionized the way of modeling human diseases, especially neurological diseases. Currently almost all types of neural cells, including but not limited to neural stem cells, neurons, astrocytes, oligodendrocytes and microglia, can be derived from iPSCs following developmental principles. These iPSC-derived neural cells provide valuable tools for studying neurological disease mechanisms, developing potential therapies, and deepening our understanding of the nervous system. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are single-stranded, non-coding RNA molecules that play important roles in the development and functions of the brain. Extensive studies have revealed critical roles for miRNAs in brain development and function. Dysregulation or altered expression of miRNAs is associated with abnormal brain development and pathogenesis of neurodevelopmental diseases. This review serves to highlight the versatile roles of these small RNA molecules in normal brain development and their association with neurodevelopmental disorders, in particular, two closely related neuropsychiatric disorders of neurodevelopmental origin, schizophrenia and bipolar disorder. [ABSTRACT FROM AUTHOR]

Abstract: The core transcriptional regulatory circuitries are important for controlling stem cell self-renewal and differentiation. Nuclear receptors provide an ideal model to regulate gene expression in both ligand-dependent and ligand-independent manners. Recent studies of regulatory events by nuclear receptors in neural stem cells, embryonic stem cells, and induced pluripotent stem cells (iPSCs) provided unique insights into mechanisms of stem cell regulation and provided invaluable resources for regenerative medicine. Nuclear receptors have been shown to be key players in stem cell self-renewal, pluripotency, and reprogramming. We summarize recent progress of studies on nuclear receptors in stem cell field as well as the potential therapeutic implications of these nuclear receptors and their cognate ligands. These studies not only uncover molecular mechanisms of stem cell regulation, but also provide unique opportunities for drug discovery. [ABSTRACT FROM AUTHOR]

Abstract: Two fundamental properties of stem cells are their ability to self-renew and to differentiate. Self-renewal is an integration of proliferation control with the maintenance of an undifferentiated state. Stem cell self-renewal is regulated by the dynamic interplay between transcription factors, epigenetic control, microRNA (miRNA) regulators, and cell-extrinsic signals from the microenvironment in which stem cells reside. Recent progress in defining specific roles for cell-intrinsic factors and extrinsic factors in regulating stem cell self-renewal starts to unfold the multilayered regulatory networks. This review focuses on cell-intrinsic regulators, including orphan nuclear receptor TLX, polycomb transcriptional repressor Bmi1, high-mobility-group DNA binding protein Sox2, basic helix-loop-helix Hes genes, histone modifying enzymes and chromatin remodeling proteins, and small RNA modulators, as well as cell-extrinsic signaling molecules, such as Wnt, Notch, Sonic hedgehog (Shh), TGFα, EGF, and FGF. Unraveling the mechanisms by which neural stem cells renew themselves will provide insights into both basic neurosciences and clinical applications of stem cell-based cell replacement therapies for neurodegenerative diseases. [Copyright &y& Elsevier]

The finding of neurogenesis in the adult brain led to the discovery of adult neural stem cells. TLX was initially identified as an orphan nuclear receptor expressed in vertebrate forebrains and is highly expressed in the adult brain. The brains of TLX-null mice have been reported to have no obvious defects during embryogenesis; however, mature mice suffer from retinopathies, severe limbic defects, aggressiveness, reduced copulation and progressively violent behaviour. Here we show that TLX maintains adult neural stem cells in an undifferentiated, proliferative state. We show that TLX-expressing cells isolated by fluorescence-activated cell sorting (FACS) from adult brains can proliferate, self-renew and differentiate into all neural cell types in vitro. By contrast, TLX-null cells isolated from adult mutant brains fail to proliferate. Reintroducing TLX into FACS-sorted TLX-null cells rescues their ability to proliferate and to self-renew. In vivo, TLX mutant mice show a loss of cell proliferation and reduced labelling of nestin in neurogenic areas in the adult brain. TLX can silence glia-specific expression of the astrocyte marker GFAP in neural stem cells, suggesting that transcriptional repression may be crucial in maintaining the undifferentiated state of these cells. [ABSTRACT FROM AUTHOR]

The authors comment on the process of neurogenesis and neural stem cells (NSCs) in microRNAs (miRNAs). They refer to several articles that analyze the diverse roles miRNA play in neurogenesis. The generation of new born neuronal cells from NSCs and progenitor cells in the mammalian brain constitutes the process of neurogenesis.