Jianwei Jiao

Induction of Neurogenesis in Nonconventional Neurogenic Regions of the Adult Central Nervous System by Niche Astrocyte-Produced Signals

The central nervous system (CNS) of adult mammals regenerates poorly; in vivo, neurogenesis occurs only in two restricted areas, the hippocampal subgranular zone (SGZ) and the subventricular zone (SVZ). Neurogenic potential depends on both the intrinsic properties of neural progenitors and the environment, or niche, in which progenitor cells reside. Isolation of multipotent progenitor cells from broad CNS regions suggests that the neurogenic potential of the adult CNS is dictated by local environmental cues. Here, we report that astrocytes in the neurogenic brain regions, the SGZ and SVZ, of adult mice release molecular signals, such as sonic hedgehog (Shh), that stimulate adult neural progenitors to reenter the cell cycle and generate new neurons in vitro and in vivo. Transplantation of SGZ astrocytes or application of Shh caused de novo neurogenesis from the non‐neurogenic neocortex of adult mice. These findings identify a molecular target that can activate the dormant neurogenic potential from nonconventional neurogenic regions of the adult CNS and suggest a novel mechanism of neural replacement therapy for treating neurodegenerative disease and injury without transplanting exogenous cells.

Bcl‐2 enhances Ca2+ signaling to support the intrinsic regenerative capacity of CNS axons

At a certain point in development, axons in the mammalian CNS undergo a profound loss of intrinsic growth capacity, which leads to poor regeneration after injury. Overexpression of Bcl‐2 prevents this loss, but the molecular basis of this effect remains unclear. Here, we report that Bcl‐2 supports axonal growth by enhancing intracellular Ca2+ signaling and activating cAMP response element binding protein (CREB) and extracellular‐regulated kinase (Erk), which stimulate the regenerative response and neuritogenesis. Expression of Bcl‐2 decreases endoplasmic reticulum (ER) Ca2+ uptake and storage, and thereby leads to a larger intracellular Ca2+ response induced by Ca2+ influx or axotomy in Bcl‐2‐expressing neurons than in control neurons. Bcl‐xL, an antiapoptotic member of the Bcl‐2 family that does not affect ER Ca2+ uptake, supports neuronal survival but cannot activate CREB and Erk or promote axon regeneration. These results suggest a novel role for ER Ca2+ in the regulation of neuronal response to injury and define a dedicated signaling event through which Bcl‐2 supports CNS regeneration.

Ephrins as negative regulators of adult neurogenesis in diverse regions of the central nervous system

In the central nervous system (CNS) of adult mammals, neurogenesis occurs in only two restricted areas, the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ). Isolation of multipotent progenitor cells from other CNS regions suggests that their neurogenic potential is dictated by local environmental cues. Here, we report that astrocytes in areas outside of the SGZ and SVZ of adult mice express high levels of ephrin-A2 and -A3, which present an inhibitory niche, negatively regulating neural progenitor cell growth. Adult mice lacking both ephrin-A2 and -A3 display active ongoing neurogenesis throughout the CNS. These findings suggest that neural cell replacement therapies for neurodegeneration or injury in the adult CNS may be achieved by manipulating ephrin signaling pathways.

Ezh2 Regulates Adult Hippocampal Neurogenesis and Memory

Adult neurogenesis is thought to be crucial for preserving cognitive functions, which is tightly controlled by various epigenetic regulators. As the methyltransferase of histone H3K27, the role of Ezh2 in neurogenesis of adult mice and its mechanism of action are largely unknown. Here, we show that Ezh2 is expressed in actively dividing neural stem cells (NSCs)/progenitor cells as well as mature neurons, but not in quiescent NSCs in the subgranular zone. The deletion of Ezh2 in NSCs/progenitor cells results in a reduction in progenitor cell proliferation. Furthermore, we found that Ezh2 regulates progenitor cell proliferation by suppressing Pten expression and promoting the activation of Akt-mTOR. Moreover, the loss of Ezh2 in progenitor cells leads to a decrease in the number of neurons, which was observed by long-term tracing. Strikingly, conditional knockout of Ezh2 ultimately results in impairments in spatial learning and memory, contextual fear memory, and pattern separation. Our findings demonstrate the essential role of Ezh2 in the proliferation of progenitor cells, thus providing insight into the molecular mechanisms of adult neurogenesis in preserving cognitive functions.

Resolvin D1 and Aspirin-Triggered Resolvin D1 Regulate Histamine-stimulated Conjunctival Goblet Cell Secretion

Resolution of inflammation is an active process mediated by pro-resolution lipid mediators. As resolvin (Rv) D1 is produced in the cornea, pro-resolution mediators could be effective in regulating inflammatory responses to histamine in allergic conjunctivitis. Two key mediators of resolution are the D-series resolvins RvD1 or aspirin-triggered RvD1 (AT-RvD1). We used cultured conjunctival goblet cells to determine whether histamine actions can be terminated during allergic responses. We found cross-talk between two types of G protein-coupled receptors (GPRs), as RvD1 interacts with its receptor GPR32 to block histamine-stimulated H1 receptor increases in intracellular [Ca2+] ([Ca2+]i) preventing H1 receptor-mediated responses. In human and rat conjunctival goblet cells, RvD1 and AT-RvD1 each block histamine-stimulated secretion by preventing its increase in [Ca2+]i and activation of extracellular regulated–protein kinase (ERK)1/2. We suggest that D-series resolvins regulate histamine responses in the eye and offer new treatment approaches for allergic conjunctivitis or other histamine-dependent pathologies.

MicroRNA‐15b promotes neurogenesis and inhibits neural progenitor proliferation by directly repressing TET3 during early neocortical development

MicroRNAs (miRNAs) are important regulators of mouse brain development. However, their precise roles in this context remain to be elucidated. Through screening of expression profiles from a miRNA microarray and experimental analysis, we show here that miR‐15b controls several aspects of cortical neurogenesis. miR‐15b inhibits cortical neural progenitor cell (NPC) proliferation and promotes cell‐cycle exit and neuronal differentiation. Additionally, miR‐15b expression decreases the number of apical progenitors and increases basal progenitors in the VZ/SVZ. We also show that miR‐15b binds to the 3′ UTR of TET3, which plays crucial roles during embryonic development by enhancing DNA demethylation. TET3 promotes cyclin D1 expression, and miR‐15b reduces TET3 expression and 5hmC levels. Notably, TET3 expression rescues miR‐15b‐induced impaired NPC proliferation and increased cell‐cycle exit in vivo. Our results not only reveal a link between miRNAs, TET, and DNA demethylation but also demonstrate critical roles for miR‐15b and TET3 in maintaining the NPC pool during early neocortical development.

The Crucial Role of Atg5 in Cortical Neurogenesis During Early Brain Development

Autophagy plays an important role in the central nervous system. However, it is unknown how autophagy regulates cortical neurogenesis during early brain development. Here, we report that autophagy-related gene 5 (Atg5) expression increased with cortical development and differentiation. The suppression of Atg5 expression by knockdown led to inhibited differentiation and increased proliferation of cortical neural progenitor cells (NPCs). Additionally, Atg5 suppression impaired cortical neuronal cell morphology. We lastly observed that Atg5 was involved in the regulation of the β-Catenin signaling pathway. The β-Catenin phosphorylation level decreased when Atg5 was blocked. Atg5 cooperated with β-Catenin to modulate cortical NPCs differentiation and proliferation. Our results revealed that Atg5 has a crucial role in cortical neurogenesis during early embryonic brain development, which may contribute to the understanding of neurodevelopmental disorders caused by autophagy dysregulation.

The role of microRNAs in neural stem cells and neurogenesis.

Neural stem cells give rise to neurons through the process of neurogenesis, which includes neural stem cell proliferation, fate determination of new neurons, as well as the new neurons migration, maturation and integration. Currently, neurogenesis is divided into two phases: embryonic and adult phases. Embryonic neurogenesis occurs at high levels to form the central nervous system. Adult neurogenesis has been consistently identified only in restricted regions and occurs at low levels. As the basic process for embryonic neurodevelopment and adult brain maintenance, neurogenesis is tightly regulated by many factors and pathways. MicroRNA, short non-coding RNA that regulates gene expression at the post-transcriptional level, appears to be involved in multiple steps of neurogenesis. This review summarizes the emerging role of microRNAs in regulating embryonic and adult neurogenesis, with a particular emphasis on the proliferation and differentiation of neural stem cells.

CHD2 is Required for Embryonic Neurogenesis in the Developing Cerebral Cortex

Chromodomain helicase DNA‐binding protein 2 (CHD2) has been associated with a broad spectrum of neurodevelopmental disorders, such as autism spectrum disorders and intellectual disability. However, it is largely unknown whether and how CHD2 is involved in brain development. Here, we demonstrate that CHD2 is predominantly expressed in Pax6+ radial glial cells (RGs) but rarely expressed in Tbr2+ intermediate progenitors (IPs). Importantly, the suppression of CHD2 expression inhibits the self‐renewal of RGs and increases the generation of IPs and the production of neurons. CHD2 mediates these functions by directly binding to the genomic region of repressor element 1‐silencing transcription factor (REST), thereby regulating the expression of REST. Furthermore, the overexpression of REST rescues the defect in neurogenesis caused by CHD2 knockdown. Taken together, these findings demonstrate an essential role of CHD2 in the maintenance of the RGs self‐renewal levels, the subsequent generation of IPs, and neuronal output during neurogenesis in cerebral cortical development, suggesting that inactivation of CHD2 during neurogenesis might contribute to abnormal neurodevelopment. Stem Cells 2015;33:1794–1806

ATG3-dependent autophagy mediates mitochondrial homeostasis in pluripotency acquirement and maintenance.

ABSTRACT Pluripotent stem cells, including induced pluripotent and embryonic stem cells (ESCs), have less developed mitochondria than somatic cells and, therefore, rely more heavily on glycolysis for energy production.1-3 However, how mitochondrial homeostasis matches the demands of nuclear reprogramming and regulates pluripotency in ESCs is largely unknown. Here, we identified ATG3-dependent autophagy as an executor for both mitochondrial remodeling during somatic cell reprogramming and mitochondrial homeostasis regulation in ESCs. Dysfunctional autophagy by Atg3 deletion inhibited mitochondrial removal during pluripotency induction, resulting in decreased reprogramming efficiency and accumulation of abnormal mitochondria in established iPSCs. In Atg3 null mouse ESCs, accumulation of aberrant mitochondria was accompanied by enhanced ROS generation, defective ATP production and attenuated pluripotency gene expression, leading to abnormal self-renewal and differentiation. These defects were rescued by reacquisition of wild-type but not lipidation-deficient Atg3 expression. Taken together, our findings highlight a critical role of ATG3-dependent autophagy for mitochondrial homeostasis regulation in both pluripotency acquirement and maintenance.