Xiaotong Tang

Bergmann Glia Function in Granule Cell Migration During Cerebellum Development

Granule cell migration influences the laminar structure of the cerebellum and thereby affects cerebellum function. Bergmann glia are derived from radial glial cells and aid in granule cell radial migration by providing a scaffold for migration and by mediating interactions between Bergmann glia and granule cells. In this review, we summarize Bergmann glia characteristics and the mechanisms underlying the effect of Bergmann glia on the radial migration of granule neurons in the cerebellum. Furthermore, we will focus our discussion on the important factors involved in glia-mediated radial migration so that we may elucidate the possible mechanistic pathways used by Bergmann glia to influence granule cell migration during cerebellum development.

Stem-Cell Challenges in the Treatment of Alzheimer's Disease: A Long Way from Bench to Bedside

Alzheimers disease (AD) is the most prevalent type of dementia, and its neuropathology is characterized by deposition of insoluble β‐amyloid peptides, intracellular neurofibrillary tangles, and the loss of diverse neurons. Current pharmacological treatments for AD relieve symptoms without affecting the major pathological characteristics of the disease. Therefore, it is essential to develop new and effective therapies. Stem‐cell types include tissue‐specific stem cells, such as neural stem cells and mesenchymal stem cells, embryonic stem cells derived from blastocysts, and induced pluripotent stem cells (iPSCs) reprogrammed from somatic cells. Recent preclinical evidence suggests that stem cells can be used to treat or model AD. The mechanisms of stem cell based therapies for AD include stem cell mediated neuroprotection and trophic actions, antiamyloidogenesis, beneficial immune modulation, and the replacement of the lost neurons. iPSCs have been recently used to model AD, investigate sporadic and familial AD pathogenesis, and screen for anti‐AD drugs. Although considerable progress has been achieved, a series of challenges must be overcome before stem cell based cell therapies are used clinically for AD patients. This review highlights the recent experimental and preclinical progress of stem‐cell therapies for AD, and discusses the translational challenges of their clinical application.

LXR Agonists: New Potential Therapeutic Drug for Neurodegenerative Diseases

Liver X receptors (LXRs) are nuclear receptors involved in the regulation of lipid metabolism and inflammatory responses in the central nervous system. Defects in cholesterol homeostasis contribute to the pathogenesis of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and Huntington’s disease. Inflammatory responses could enhance the neurodegenerative process or act independently. The natural and synthetic LXR agonists induce the transcriptional activity of LXR target genes, thus attenuate the imbalance of cholesterol metabolism and overactivation of microglia and astrocytes in inflammation and are widely used in a variety of neurodegenerative diseases animal models. By developing more specific, potent, penetrable, and functional LXR agonist may lead to a better curative effect for neurodegenerative diseases and avoidance of potentially deleterious side effects. Here, we focus on recent advances in our understanding of the role of LXRs and their agonists in cholesterol homeostasis, inflammation, and the potential therapeutic effects in neurodegenerative diseases.

Liver X receptor β is essential for the differentiation of radial glial cells to oligodendrocytes in the dorsal cortex

Several psychiatric disorders are associated with aberrant white matter development, suggesting oligodendrocyte and myelin dysfunction in these diseases. There are indications that radial glial cells (RGCs) are involved in initiating myelination, and may contribute to the production of oligodendrocyte progenitor cells (OPCs) in the dorsal cortex. Liver X receptors (LXRs) are involved in maintaining normal myelin in the central nervous system (CNS), however, their function in oligodendrogenesis and myelination is not well understood. Here, we demonstrate that loss of LXRβ function leads to abnormality in locomotor activity and exploratory behavior, signs of anxiety and hypomyelination in the corpus callosum and optic nerve, providing in vivo evidence that LXRβ deletion delays both oligodendrocyte differentiation and maturation. Remarkably, along the germinal ventricular zone-subventricular zone and corpus callosum there is reduced OPC production from RGCs in LXRβ−/− mice. Conversely, in cultured RGC an LXR agonist led to increased differentiation into OPCs. Collectively, these results suggest that LXRβ, by driving RGCs to become OPCs in the dorsal cortex, is critical for white matter development and CNS myelination, and point to the involvement of LXRβ in psychiatric disorders.

Activation of Liver X Receptor Is Protective Against Ethanol-Induced Developmental Impairment of Bergmann Glia and Purkinje Neurons in the Mouse Cerebellum

Cerebellar Purkinje cell and granule cell development are coordinated by Bergmann glia, and are particularly sensitive to ethanol (EtOH) exposure. The liver X receptor (LXR) plays important roles in Bergmann glial development. However, the effect of LXR activation on EtOH-mediated impairment of Bergmann glia and subsequently on Purkinje cell dendritogenesis remains undetermined. Therefore, using immunohistochemistry, quantitative real-time PCR and Western blot, we tested the possible protection of LXR agonist T0901317 (T0) on Bergmann glia and Purkinje cell dendritogenesis in mice exposed to ethanol. Results showed that a brief exposure of EtOH on postnatal day (PD 5) significantly decreased the average body weight of mice at PD 6 without alteration in the brain weight. In EtOH-exposed mice, the number of migrating granule cells in the molecular layer was significantly decreased, and this effect was attenuated by pretreatment of T0. EtOH exposure also resulted in the significant reduction of calbindin-labeled Purkinje cells, their maximum dendrite length, and impairment of Purkinje cell dendritogenesis. Furthermore, EtOH induced the activation of microglia in the Purkinje cell layer and impaired the development of Bergmann glia. However, pretreatment of T0 effectively blocked all of these responses. These responses were found to be mediated by the inhibition of upregulated levels of β-catenin and transcription factor LEF1 in the cerebellum. Overall, the results suggest that activating LXRs on postnatal mice exposed to EtOH is protective to Bergmann glia, and thus may play a critical role in preventing EtOH-induced defects during cerebellar development.

Radial Glia, the Keystone of the Development of the Hippocampal Dentate Gyrus

The morphogenesis of the dentate gyrus (DG) of the hippocampus primarily occurs postnatally, and the DG is one of the few regions of continuous neurogenesis in the adult brain. Radial glial cells (RGCs), which contribute to DG development by participating in key steps of morphogenesis, are maintained in the subgranular zone (SGZ), where they play pivotal roles in adult hippocampal neurogenesis. It is clear that a series of molecules control the development of RGCs, thereby regulating the morphogenesis of the DG and neurogenesis in the adult hippocampus. In this review, we provide an updated framework regarding the molecular mechanisms involved in the development of RGCs during DG morphogenesis and discuss the key steps that regulate DG formation.

Estrogen modulation of calretinin and BDNF expression in midbrain dopaminergic neurons of ovariectomised mice

Estrogen attenuates the loss of dopamine neurons from the substantia nigra in animal models of Parkinsons disease (PD) and excitatory amino-acid induced neurotoxicity by interactions with brain-derived neurotrophic factor (BDNF), and calretinin (CR) containing dopaminergic (DA) neurons. To examine this interaction more closely, we treated the ovariectomised (OVX) mice with estrodial for 10days, and compared these mice to those OVX mice injected with the vehicle or control mice. Estrogen treatment in OVX mice had significantly more tyrosine hydroxylase (TH) positive neurons in the substantia nigra pars compacta (SNpc). Dopamine transporter (DAT) mRNA and BDNF mRNA levels in the midbrain were also significantly increased by estrogen treatment (P<0.05). OVX markedly decreased the number of TH/CR double stained cells in the SNpc (P<0.05), a trend which could be reversed by estrogen treatment. However, the number of GFAP positive cells in the substantia nigra did not show significant changes (P >0.05) after vehicle or estrodial treatment. Furthermore, we found that estrogen treatment abrogated the OVX-induced decrease in the phosphorylated AKT (p-AKT), but not p-ERK. We hypothesize that short-term treatment with estrogen confers neuroprotection to DA neurons by increasing CR in the DA neurons and BDNF in the midbrain, which possibly related to activation of the PI3K/Akt signaling pathway.

Liver X receptor β delays transformation of radial glial cells into astrocytes during mouse cerebral cortical development

Radial glial (RG) cells serve as stem cells to produce new born neurons and scaffolds for neuronal migration during corticogenesis. After neurogenesis and migration are completed, most RG cells transform into astrocytes. However, the mechanisms that determine how RG cells are transformed into astrocytes are not well understood. Using nestin as a specific marker for both RG cells and astrocytes, we found that loss of LXRβ caused a reduction in the level of RG fibers and increase in the astrocytes. At the same time, we showed that the level of brain lipid-binding protein (BLBP), a RG-specific protein, was lower in the LXRβ knockout (LXRβ(-/-)) mice than in the wild type (WT) littermates from E18.5 to P14, a time period when most of RG cells are transformed into astrocytes. However, loss of LXRβ induced significant increase in the number of GFAP labeled astrocytes in the cerebral cortex. An increase of the transformation of RG cells into astrocytes in LXRβ(-/-) mice was further confirmed by the increased percentage of BLBP and GFAP double stained cells in the total BLBP positive cells of the Layer I and Layers V-VI. TGF-β1 and Smad4 are thought to be involved in the transformation of RG cells into astrocytes. The expression levels of TGF-β1mRNA and Smad4 mRNA were significantly higher in the cerebral cortex of LXRβ(-/-) mice than that in the WT littermates at P2 and P7, but by P10 and P14, mRNA levels had normalized and no differences were observed between WT and LXRβ(-/-) mice. Taken together, our findings suggest that loss of LXRβ accelerates the transformation of RG cells into astrocytes and that this acceleration may be correlated to higher levels TGF-β1 and Smad4 in the cerebral cortex between P2 and P7.

Liver X receptor β regulates the development of the dentate gyrus and autistic-like behavior in the mouse

Significance Defects in the neurogenesis of the dentate gyrus (DG) seem to be involved in the genesis of autism spectrum disorders (ASD)-like behaviors. Our study reveals that deletion of the Liver X receptor β (LXRβ) in mice causes hypoplasia in the DG, including abnormalities in the formation of progenitor cells and reduced neurogenesis. Behavioral analysis of LXRβ-deficient mice showed autistic-like behaviors, including social interaction deficits and repetitive behavior. These findings provide evidence that early changes in DG neurogenesis is possibly associated with the genesis of autism-related behaviors in LXRβ-deficient mice. The dentate gyrus (DG) of the hippocampus is a laminated brain region in which neurogenesis begins during early embryonic development and continues until adulthood. Recent studies have implicated that defects in the neurogenesis of the DG seem to be involved in the genesis of autism spectrum disorders (ASD)-like behaviors. Liver X receptor β (LXRβ) has recently emerged as an important transcription factor involved in the development of laminated CNS structures, but little is known about its role in the development of the DG. Here, we show that deletion of the LXRβ in mice causes hypoplasia in the DG, including abnormalities in the formation of progenitor cells and granule cell differentiation. We also found that expression of Notch1, a central mediator of progenitor cell self-renewal, is reduced in LXRβ-null mice. In addition, LXRβ deletion in mice results in autistic-like behaviors, including abnormal social interaction and repetitive behavior. These data reveal a central role for LXRβ in orchestrating the timely differentiation of neural progenitor cells within the DG, thereby providing a likely explanation for its association with the genesis of autism-related behaviors in LXRβ-deficient mice.

ERβ may contribute to the maintaining of radial glia cells polarity through cadherins during corticogenesis

Laminar organization of neurons in cerebral cortex is essential for normal brain function. Radial glial cells (RGCs), are highly polarized cells that serve as neuronal progenitors and as scaffolds for neuronal migration during construction of the cerebral cortex. Cadherins (E-cadherin and N-cadherin)-based adherins junctions, which anchor apical end-feet of adjacent RGCs to each other at the ventricular surface contribute to sustain the polarity and adhesion of RGCs, therefore affect production of RGCs and radial migration. Estrogen is a steroid hormone and contributes to the organizational sexual differentiation of the brain. We have previously demonstrated that ERβ expression in the cerebral cortex during corticogenesis and contribute to cerebral cortex development. This has been further confirmed by studies from estrogen receptor β knockout (ERβKO) mice, in which lack of ERβ in mice induced abnormal development of cerebral cortical structure, retarded migration of the neurons, and abnormal morphology of RGCs with truncated or less organized radial processes. These indicate that estrogen via ERβ affects RGCs development. Moreover, phenotype analysis in the ERβKO mice has confirmed that estrogen activation ERβ influence the polarity of epithelial tissue and structure integrity by modulating the level of cadherins (E-cadherin and N-cadherin). Thus, we propose that ERβ maybe affect the maintaining the polarity of RGCs through cadherins.