The re-emergence of Zika virus (ZIKV), a mosquito-borne and sexually transmitted flavivirus circulating in > 70 countries and territories, poses a significant global threat to public health due to its ability to cause severe developmental defects in the human brain, such as microcephaly. Since the World Health Organization declared the ZIKV outbreak a Public Health Emergency of International Concern, remarkable progress has been made to gain insight into cellular targets, pathogenesis, and underlying biological mechanisms of ZIKV infection. Here we review the current knowledge and progress in understanding the impact of ZIKV exposure on the mammalian brain development and discuss potential underlying mechanisms.
Homeostatic regulation is essential for the maintenance of synaptic strength within the physiological range. The current study is the first to demonstrate that both induction and reversal of homeostatic upregulation of synaptic vesicle release can occur within seconds of blocking or unblocking acetylcholine receptors at the mouse neuromuscular junction. Our data suggest that the homeostatic upregula-tion of release is due to Ca2+-dependent increase in the size of the readily releasable pool (RRP). Blocking vesicle refilling prevented upregulation of quantal content (QC), while leaving baseline release relatively unaffected. This suggested that the upregulation of QC was due to mobilization of a distinct pool of vesicles that were rapidly recycled and thus were dependent on continued vesicle refilling. We term this pool the “homeostatic reserve pool.” A detailed analysis of the time course of vesicle release triggered by a presynaptic action potential suggests that the homeostatic reserve pool of vesicles is normally released more slowly than other vesicles, but the rate of their release becomes similar to that of the major pool during homeostatic upregulation of QC. Remarkably, instead of finding a generalized increase in the recruitment of vesicles into RRP, we identified a distinct homeostatic reserve pool of vesicles that appear to only participate in synchronized release following homeostatic upregulation of QC. Once this small pool of vesicles is depleted by the block of vesicle refilling, homeostatic upregulation of QC is no longer observed. This is the first identification of the population of vesicles responsible for the blockade-induced upregulation of release previously described.
by
Jianbo Wang;
Natasha S. Hamblet;
Sharayne Mark;
Mary E. Dickinson;
Brendan C. Brinkman;
Neil Segil;
Scott E. Fraser;
Ping Chen;
John B. Wallingford;
Anthony Wynshaw-Boris
The planar cell polarity (PCP) pathway is conserved throughout evolution, but it mediates distinct developmental processes. In Drosophila, members of the PCP pathway localize in a polarized fashion to specify the cellular polarity within the plane of the epithelium, perpendicular to the apicobasal axis of the cell. In Xenopus and zebrafish, several homologs of the components of the fly PCP pathway control convergent extension. We have shown previously that mammalian PCP homologs regulate both cell polarity and polarized extension in the cochlea in the mouse. Here we show, using mice with null mutations in two mammalian Dishevelled homologs, Dvl1 and Dvl2, that during neurulation a homologous mammalian PCP pathway regulates concomitant lengthening and narrowing of the neural plate, a morphogenetic process defined as convergent extension. Dvl2 genetically interacts with Loop-tail, a point mutation in the mammalian PCP gene Vangl2, during neurulation. By generating Dvl2 BAC (bacterial artificial chromosome) transgenes and introducing different domain deletions and a point mutation identical to the dsh1 allele in fly, we further demonstrated a high degree of conservation between Dvl function in mammalian convergent extension and the PCP pathway in fly. In the neuroepithelium of neurulating embryos, Dvl2 shows DEP domain-dependent membrane localization, a pre-requisite for its involvement in convergent extension. Intriguing, the Loop-tail mutation that disrupts both convergent extension in the neuroepithelium and PCP in the cochlea does not disrupt Dvl2 membrane distribution in the neuroepithelium, in contrast to its drastic effect on Dvl2 localization in the cochlea. These results are discussed in light of recent models on PCP and convergent extension.
Cell-based therapies are a viable option for the long-term treatment of Huntington's disease (HD), which is characterized by progressive neurodegeneration predominately in the striatum and cortex. Current research focuses on genetic suppression of the mutant huntingtin (mHTT) gene and cell replacement therapy of the lost cells in HD. As we discuss here, the recent development of induced pluripotent stem (iPS) cells technology demonstrated the potential of cell-based therapy in rodent models. It was shown that iPSCs were capable of differentiating into lost neurons in HD and stem cell grafts can improve motor deficiency in HD rodent models. Altogether, these findings have shown great promise for developing the foundation of the cell-based therapy.
by
Yonggang Zhang;
Jianjun Liu;
Shaohua Yao;
Fang Li;
Lin Xin;
Mowen Lai;
Valerie Bracchi-Ricard;
Hong Xu;
William Yen;
Wentong Meng;
Shu Liu;
Leiting Yang;
Shaffiat Karmally;
Jin Liu;
Hongyan Zhu;
Jennifer Gordon;
Kamel Khalili;
Shanthi Srinivasan;
John R. Bethea;
Xianming Mo;
Wenhui Hu
Inflammatory mediators, many of which activate the signaling of nuclear factor kappa B (NFκB), have received increasing attention in the field of neurogenesis. NFκB signaling regulates neurite outgrowth and neural plasticity as well as the proliferation/apoptosis and terminal differentiation of neural stem cells (NSCs). Early neurogenesis from NSCs produces identical progeny through symmetric division and committed daughter cells through asymmetric division. Here, we show that NFκB signaling is required for NSC initial differentiation. The canonical IKKβ/IκBα/ p65 pathway is activated during the initial stages of neural differentiation induced by treatment with TNFα or withdrawal of epidermal growth factor/basic fibroblast growth factor. NSC-specific inhibition of NFκB in transgenic mice causes an accumulation of Nestin+/Sox2+/glial fibrillary acidic protein+NSCs. Inhibition of NFκB signaling in vitro blocks differentiation and asymmetric division and maintains NSCs in an undifferentiated state. The induction of initial differentiation and asymmetry by NFκB signaling occurs through the inhibition of C/EBPβ expression. Our data reveal a novel function of NFκB signaling in early neurogenesis and provide insight into the molecular mechanisms underlying neurodevelopmental disorders and neurodegenerative diseases.
In the embryonic and adult brain, neural stem cells proliferate and give rise to neurons and glia through highly regulated processes. Epigenetic mechanisms-including DNA and histone modifications, as well as regulation by non-coding RNAs-have pivotal roles in different stages of neurogenesis. Aberrant epigenetic regulation also contributes to the pathogenesis of various brain disorders. Here, we review recent advances in our understanding of epigenetic regulation in neurogenesis and its dysregulation in brain disorders, including discussion of newly identified DNA cytosine modifications. We also briefly cover the emerging field of epitranscriptomics, which involves modifications of mRNAs and long non-coding RNAs.