Neurogenesis (Austin, Tex.)最新文献

Astrocytes, a major type of glial cells in the mammalian central nervous system (CNS), have a wide variety of physiological functions, including formation of the blood brain barrier, and modulation of synaptic transmission and information processing, and maintenance of CNS homeostasis. The signaling pathway initiated by bone morphogenetic protein (BMP) is critical for astrogliogenesis. However, exactly how this pathway regulates astrogliogenesis remains poorly understood. We have recently provided in vitro and in vivo evidence for neogenin's function in neural stem cells (NSCs) to promote neocortical astrogliogenesis. Neogenin in NSCs as well as astrocytes is required for BMP2 activation of RhoA that promotes YAP (yes-associated protein) nuclear translocation, consequently, YAP interaction with nuclear p-Smad1/5/8, and stabilization of Smad1/5/8 signaling. We have also provided evidence that YAP in NSCs is necessary for neocortical astrogliogenesis, and expression of YAP in neogenin deficient NSCs diminishes the astrogliogenesis deficit. These recent findings identify an unrecognized function of neogenin in promoting neocortical astrogliogenesis, and reveal a pathway of BMP2-neogenin-YAP-Smad1 underlying astrogliogenesis in developing mouse neocortex.

The latest miRNA database (Release 21) annotated 2588 and 1915 miRNAs in the human and mouse genomes, respectively.¹ However, the biological roles of miRNAs in vivo remain largely unknown. In particular, the physiological and pathological roles of individual microRNAs in the brain have not been investigated extensively although expression profiles of microRNAs have been reported in many given conditions. In a recent study,² we identified miR-19, which is enriched in adult hippocampal neural progenitor cells (NPCs), as a key regulator for adult hippocampal neurogenesis. miR-19 is an intrinsic factor regulating the migration of newborn neurons by modulating expression level of RAPGEF2. After observing the abnormal expression patterns of miR-19 and RAPGEF2 in NPCs derived from induced pluripotent stem cells of schizophrenic patients, which display aberrant cell migration, we proposed miR-19 as a molecule associated with schizophrenia. The results illustrate that a single microRNA has the potential to impact the functions of the brain. Identifying miRNA-mediated posttranscriptional gene regulation in the brain will expand our understanding of brain development and functions and the etiologies of several brain disorders.

In the developing mammalian neocortex, newborn neurons produced deep in the brain from neural stem/progenitor cells set out for a long journey to reach their final destination at the brain surface. This process called radial neuronal migration is prerequisite for the formation of appropriate layers and networks in the cortex, and its dysregulation has been implicated in cortical malformation and neurological diseases. Considering a fine correlation between temporal order of cortical neuronal cell types and their spatial distribution, migration speed needs to be tightly controlled to achieve correct neocortical layering, although the underlying molecular mechanisms remain not fully understood. Recently, we discovered that the kinase Akt and its activator PDK1 regulate the migration speed of mouse neocortical neurons through the cortical plate. We further found that the PDK1-Akt pathway controls coordinated movement of the nucleus and the centrosome during migration. Our data also suggested that control of neuronal migration by the PDK1-Akt pathway is mediated at the level of microtubules, possibly through regulation of the cytoplasmic dynein/dynactin complex. Our findings thus identified a signaling pathway controlling neuronal migration speed as well as a novel link between Akt signaling and cytoplasmic dynein/dynactin complex.

Parkinson's disease (PD), a neurodegenerative disorder characterized by the selective degeneration of the nigrostriatal dopaminergic pathway, is a major socio-economic burden in modern society. While there is presently no cure for PD, enhancing the number of neural stem cells (NSCs) and/or stimulating their differentiation into new neurons are promising therapeutic strategies. Many proneurogenic factors have been implicated in controlling NSCs activity, including the microRNA (miR)-124. However, current strategies described for the intracellular delivery of miR involve mostly unspecific or inefficient platforms. In Saraiva et al. we developed miR-124 loaded nanoparticles (NPs) able to efficiently deliver miR-124 into neural stem/progenitor cells and boost neuronal differentiation and maturation in vitro. In vivo, the intracerebroventricular injection of miR-124 NPs increased the number of new neurons in the olfactory bulb of healthy and 6-hydroxidopamine (6-OHDA) lesioned mice, a model for PD. Importantly, miR-124 NPs enhanced the migration of new neurons into the 6-OHDA lesioned striatum, culminating in motor function improvement. Given the recent advent of clinical trials for miR-based therapies and the theranostic applications of our NPs, we expect to support the clinical translation of our delivery platform in the context of PD and other neurodegenerative diseases which may benefit from enhancing miR levels.

Adult spinal cord neurogenesis occurs at low, constant rate under normal conditions and can be amplified by pathologic conditions such as injury or disease. The immature neurons produced through adult neurogenesis have increased excitability and migrate preferentially to the superficial dorsal horn layers responsible for nociceptive signaling. Under normal conditions, this process may be responsible for maintaining a steady-state, but adaptable level of nociceptive sensitivity, thus representing an experience-dependent mechanism of regulation similar to other neurogenic niches. Under pathologic conditions, adult spinal cord neurogenesis is greatly amplified and may therefore account for the observed changes in general spinal cord excitability and nociceptive sensitivity. This mechanism also explains many types of chronic pain present in the absence of injury or disease, which may be the result of impaired neuronal differentiation due to a variety of genetic variations. This suggests the possibility of using promoters of neuronal differentiation for the long-term treatment of the causes of chronic pain, unlike current medication which is palliative and effective only for the duration of treatment. The presence of this spinal cord neurogenic niche may also lead to new approaches in spinal cord regeneration.

In the adult brain, increases in local neural activity are accompanied by increases in regional blood flow. This relationship between neural activity and hemodynamics is termed neurovascular coupling and provides the blood flow-dependent contrast detected in functional magnetic resonance imaging (fMRI). Neurovascular coupling is commonly assumed to be consistent and reliable from birth; however, numerous studies have demonstrated markedly different hemodynamics in the early postnatal brain. Our recent study in J. Neuroscience examined whether different hemodynamics in the immature brain are driven by differences in the underlying spatiotemporal properties of neural activity during this period of robust neural circuit expansion. Using a novel wide-field optical imaging technique to visualize both neural activity and hemodynamics in the mouse brain, we observed longer duration and increasingly complex patterns of neural responses to stimulus as cortical connectivity developed over time. However, imaging of brain blood flow, oxygenation, and metabolism in the same mice demonstrated an absence of coupled blood flow responses in the newborn brain. This lack of blood flow coupling was shown to lead to oxygen depletions following neural activations - depletions that may affect the duration of sustained neural responses and could be important to the vascular patterning of the rapidly developing brain. These results are a step toward understanding the unique neurovascular and neurometabolic environment of the newborn brain, and provide new insights for interpretation of fMRI BOLD studies of early brain development.

The expansion of outer radial glia (oRGs, also called basal RGs) and intermediate progenitor cells (IPCs) has played a key role in the evolutionary expansion and folding of the neocortex, resulting in superior sensorimotor and cognitive abilities. In particular, oRGs, which are critical for both the increased production and lateral dispersion of neurons, are rare in lisencephalic species but vastly expanded in gyrencephalic species. However, the mechanisms that expand oRGs and IPCs are not well understood. We recently identified Sonic hedgehog (Shh) signaling as the first known signaling pathway necessary and sufficient to expand both oRGs and IPCs. Elevated Shh signaling in the embryonic neocortex leads to neocortical expansion and folding with normal cytoarchitecture in otherwise smooth mouse neocortex, whereas the loss of Shh signaling decreases oRGs, IPCs, and neocortical size. We also showed that SHH signaling activity in fetal neocortex is stronger in humans than in mice and that blocking SHH signaling decreases oRGs in human cerebral organoids. Shh signaling may be a conserved mechanism that promotes oRG and IPC expansion, driving neocortical growth and folding in humans and other species. Understanding the mechanisms underlying species-specific differences in Shh signaling activity and how Shh signaling expands oRGs and IPCs will provide insights into the mechanisms of neocortical development and evolution.

Neuronal migration is an essential step in the formation of laminated brain structures. In the developing cerebral cortex, pyramidal neurons migrate toward the Reelin-containing marginal zone. Reelin is an extracellular matrix protein synthesized by Cajal-Retzius cells. In this review, we summarize our recent results and hypotheses on how Reelin might regulate neuronal migration by acting on the actin and microtubule cytoskeleton. By binding to ApoER2 receptors on the migrating neurons, Reelin induces stabilization of the leading processes extending toward the marginal zone, which involves Dab1 phosphorylation, adhesion molecule expression, cofilin phosphorylation and inhibition of tau phosphorylation. By binding to VLDLR and integrin receptors, Reelin interacts with Lis1 and induces nuclear translocation, accompanied by the ubiquitination of phosphorylated Dab1. Eventually Reelin induces clustering of its receptors resulting in the endocytosis of a Reelin/receptor complex (particularly VLDLR). The resulting decrease in Reelin contributes to neuronal arrest at the marginal zone.

Astrocytes traditionally were thought to have merely a support function, but are now understood to be important regulators of neural development and function. The immature and mature astrocytes have stage-specific roles in neuronal development. However, it is largely unclear whether human astrocytes also serve stage-specific roles in oligodendroglial development. Owing to the broad and diverse roles of astroglia in the central nervous system, transplantation of astroglia also could be of therapeutic value in promoting regeneration after CNS injury or disease. Our recent study (Jiang et al., 2016) explores the developmental interactions between astroglia and oligodendroglia, using a human induced pluripotent stem cell (hiPSC) model. By generating immature and mature human astrocytes from hiPSCs, we reveal previously unrecognized effects of immature human astrocytes on oligodendrocyte development. Notably, tissue inhibitor of metalloproteinase-1 (TIMP-1) is differentially expressed in the immature and mature human astrocytes, and mediates at least in part the effects of immature human astrocytes on oligodendroglial differentiation. Furthermore, we demonstrate that hiPSC-derived astroglial transplants promote cerebral white matter regeneration and behavioral recovery in a neonatal mouse model of hypoxic-ischemic injury. Our study provides novel insights into the astro-oligodendroglial cell interaction and has important implications for possible therapeutic interventions for human white matter diseases.

Alternative splicing, as well as chromatin structure, greatly contributes to specific transcriptional programs that promote neuronal differentiation. The activity of G9a, the enzyme responsible for mono- and di-methylation of lysine 9 on histone H3 (H3K9me1 and H3K9me2) in mammalian euchromatin, has been widely implicated in the differentiation of a variety of cell types and tissues. In a recent work from our group (Fiszbein et al., 2016) we have shown that alternative splicing of G9a regulates its nuclear localization and, therefore, the efficiency of H3K9 methylation, which promotes neuronal differentiation. We discuss here our results in the light of a report from other group (Laurent et al. 2015) demonstrating a key role for the alternative splicing of the histone demethylase LSD1 in controlling specific gene expression in neurons. All together, these results illustrate the importance of alternative splicing in the generation of a proper equilibrium between methylation and demethylation of histones for the regulation of neuron-specific transcriptional programs.