Understanding neural stem cell behavior in the context of genetic, epi…

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  • 2017-01-06


[BK21 Plus Seminar]
                  ▶Subject: Understanding neural stem cell behavior in the context of genetic, epitranscriptomic and pathogenic alterations
                  ▶Speaker: YOON, Ki-Jun, PH.D. (Johns Hopkins University School of Medicine, Baltimore)

                  ▶Date: 3:00 PM/Oct. 4(Tue.)/2016
                  ▶Place: Life Science Bldg. #104
                    1) Modeling a risk factor for schizophrenia in human iPSCs and mice reveals neural stem cell function associated with adherens junctions and polarity
 Defects in brain development are believed to contribute towards on-set of neuropsychiatric disorders but identifying specific underlying mechanisms has proven difficult. Here, we took a multi-faceted approach to investigate why 15q11.2 copy number variants are prominent risk factors for schizophrenia and autism. First, we show that human iPSC-derived neural progenitors carrying 15q11.2 microdeletion exhibit deficits in adherens junctions and apical polarity. This results from haploinsufficiency of CYFIP1, a gene within 15q11.2 that encodes a subunit of the WAVE complex, which regulates cytoskeletal dynamics. In developing mouse cortex, deficiency in CYFIP1 and WAVE signaling similarly affects radial glial cells, leading to their ectopic localization outside of the ventricular zone. Finally, targeted human genetic association analyses revealed an epistatic interaction between CYFIP1 and WAVE signalling mediator ACTR2 and risk for schizophrenia. Our findings provide insight into how CYFIP1 regulates neural stem cell function and may contribute to the susceptibility of neuropsychiatric disorders.

2) The regulation of neural stem cell behavior through epitranscriptomic program of RNA methylation
 Post-transcriptional modifications of RNA have recently garnered interest for their regulatory roles in RNA biology. Specifically, the dynamic N6-methyladenosine (m6A) modification is abundant in mRNAs, particularly around stop codons and transcription start sites. The m6A modification has been shown to affect RNA stability, translation, translocation and splicing, though the detail molecular mechanisms remain elusive. To understand the role of m6A modification on the neural development and neural stem cell biology in vivo, we have used conditional knockout mice of Mettl14, a subunit of the methyltransferase complex that places m6A modification on mRNA. Loss of Mettl14 function in the developing cerebral cortex results in marked alteration of the proliferative and self-renewal capabilities of neural stem cells and neural progenitors. Interestingly, Mettl14-deficient cortices showed improper neuronal subtype specification and delayed onset of neurogenesis-gliogenesis transition. To identify m6A modified mRNA subsets, we applied high-throughput m6A sequencing analysis and found that m6A modification is enriched in neural stem cell specific genes and regulates their RNA stabilities. These results suggest that the epitranscriptomic program through m6A mRNA modification is a crucial intrinsic regulation of neural stem cell behaviors to ensure the proper organization of the developing mammalian brain. 

3) Studying the mechanism of Zika virus (ZIKV)-induced microcephaly using mouse model and human cerebral organoids
 Increased reports of microcephaly and other neurological disorders coinciding with clusters of ZIKV outbreaks in Brazil have aroused urgent demands to understand ZIKV pathology. Recent studies of human neural progenitor cells and organoid cultures showed efficient infection by ZIKV, leading to increased cell death and attenuated growth related with microcephaly. However, molecular mechanisms of ZIKV-induced abnormalities are largely unclear. We screened effects of individual ORFs during the brain development in vivo by in utero electroporation and identified a crucial component of ZIKV resulting in microcephaly-related phenotypes. In addition, we also utilized human 3D cerebral organoids to further understand cellular impacts of a ZIKV component on neural stem cells. By using RNA-seq analysis and protein array chip, we have identified the responsible signaling pathways underlying ZIKV pathology. Our studies will elucidate how the Zika coding genome interacts with the host and provide novel therapeutic strategies aimed to ameliorate ZIKV symptoms

                ▶Inquiry: Prof. Park, Sang Ki (279-2349)
                    * This seminar will be given in English.
                please refrain from taking photos during seminars. *