Japanese encephalitis virus (JEV) predominantly infects neurons and causes damage to the central nervous system (CNS). Neural stem/progenitor cells (NSPCs) constitute multi-potent stem cell population in postnatal/adult brain, with capacity to differentiate into neurons, astrocytes or oligodendrocytes. NSPCs are known to play a pivotal role in CNS repair mechanisms during various neurological disorders. Previous studies from our laboratory have shown that JEV infection of NSPCs depletes the stem-cell pool, which may result in impaired repair functions leading to motor and cognitive deficits in survivors. In the present study, we evaluated the effect of JEV infection on differentiation potential of NSPCs isolated from BALB/c mouse pups (Post natal day 7). Results clearly indicated that, JEV infection was more robust in undifferentiated NSPCs as compared to differentiated ones. Further, JEV infected NSPCs showed hampered differentiation and arrested migration in adherent neurosphere cultures. Interestingly, the neuronal differentiation appeared to be more severely affected by JEV as compared to astrocyte differentiation. The transcription factors involved in both neuronal and astrocyte differentiations were significantly decreased upon JEV infection. Overall, results presented in this study comprehensively provide first evidence for JEV induced alteration of neuronal and astrocyte differentiation.
Differentiation and self-renewal are two primary properties that characterize stem cells. Differentiation of neural stem/precursor cells (NSPCs) gives rise to multiple neural lineages, including neurons, astrocytes, and oligodendrocytes. Self-renewal, by definition, signifies the progressive growth of cells, while preserving an undifferentiated state. A large number of interdependent factors, including transcription factors, epigenetic control, and micro-RNA regulators, modulate these opposing processes without disrupting the regular neural network. The epigenetic modification of developmental genes, including alterations in DNA methylation, histone modifications, polycomb gene group and noncoding RNA expression, which are passed on through successive cell divisions, has proved to be one of the major mechanisms determining the fate of neural stem cells. Here, we review the diverse epigenetic pathways that decide whether NSPCs undergo proliferation or differentiation into different neuronal cell lineages.
In 1990s, reports of discovery of a small group of cells capable of proliferation and contribution to formation of new neurons in the central nervous system (CNS) reversed a century-old concept on lack of neurogenesis in the adult mammalian brain. These cells are found in all stages of human life and contribute to normal cellular turnover of the CNS. Therefore, the identity of regulating factors that affect their proliferation and differentiation is a highly noteworthy issue for basic scientists and their clinician counterparts for therapeutic purposes. The cues for such control are embedded in developmental and environmental signaling through a highly regulated tempo-spatial expression of specific transcription factors. Novel findings indicate the importance of reactive oxygen species (ROS) in the regulation of this signaling system. The elusive nature of ROS signaling in many vital processes from cell proliferation to cell death creates a complex literature in this field. Here, we discuss the emerging thoughts on the importance of redox regulation of proliferation and maintenance in mammalian neural stem and progenitor cells under physiological and pathological conditions. The current knowledge on ROS-mediated changes in redox-sensitive proteins that govern the molecular mechanisms in proliferation and differentiation of these cells is reviewed.
Mitochondria play a crucial role in neuronal survival through efficient energy metabolism. In pathological conditions, mitochondrial stress leads to neuronal death, which is regulated by the anti-apoptotic BCL-2 family of proteins. MCL-1 is an anti-apoptotic BCL-2 protein localized to mitochondria either in the outer membrane (OM) or inner membrane (Matrix), which have distinct roles in inhibiting apoptosis and promoting bioenergetics, respectively. While the antiapoptotic role for Mcl1 is well characterized, the protective function of MCL-1 Matrix remains poorly understood. Here, we show MCL-1 OM and MCL-1 Matrix prevent neuronal death through distinct mechanisms. We report that MCL-1 Matrix functions to preserve mitochondrial energy transduction and improves respiratory chain capacity by modulating mitochondrial oxygen consumption in response to mitochondrial stress. We show that MCL-1 Matrix protects neurons from stress by enhancing respiratory function, and by inhibiting mitochondrial permeability transition pore opening. Taken together, our results provide novel insight into how MCL-1 Matrix may confer neuroprotection under stress conditions involving loss of mitochondrial function.
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