探討LHX2轉錄因子在人類神經分化扮演的角色

The Role of LHX2 in Human Neural Differentiation

侯珮珊(Pei-Shan Hou)

指導教授 ： 錢宗良

國立臺灣大學/醫學院/解剖學暨生物細胞學研究所/博士(2013年)

https://doi.org/10.6342/NTU.2013.00228

摘要

無資料

關鍵字

人類胚胎幹細胞 ； 神經分化 ； LHX2 ； PAX6 ； CER1

並列摘要

The LIM homeobox 2 transcription factor LHX2 is known to control crucial aspects of neural development in various species. However, its function in human neural development is still elusive. Here, we demonstrate that LHX2 plays a critical role in human neural differentiation using hESCs as a model for differentiation. In hESC-derived neural progenitors (hESC-NPs), expression of LHX2 was prior to PAX6 and SOX1, and LHX2 was co-expressed with early neural markers. Conditional ectopic expression of LHX2 promoted the formation of neural rosette-like structures and upregulated neural transcription factor expression. Conversely, disruption of LHX2 expression by constitutive expression of LHX2 shRNA in hESCs significantly impaired neural differentiation both in vitro and in vivo. Furthermore, we demonstrated that LHX2 regulates neural differentiation in two levels, first, it promotes the expression of neurogenic gene Pax6 and second, it promotes the expression of Cerberus 1 to inhibit non-neural differentiation. LHX2 was found to regulate PAX6 expression in hESC-NPs by binding to PAX6 enhancers, which were enriched with the chromatin markers of active enhancers H3K4me1 and H3K27ac). Importantly, LHX2 was also found to attenuate BMP and WNT signaling and inhibit non-neural differentiation by augmenting the expression of BMP and WNT antagonist, Cerberus 1(CER1). Collectively, our studies provide further insights into the molecular mechanisms governing human neural differentiation, which has implications in the large-scale generation of neural cells for basic research and clinical applications.

並列關鍵字

human embryonic stem cells ； neural differentiation ； LHX2 ； PAX6 ； CER1

參考文獻

Abellan, A., A. Menuet, C. Dehay, L. Medina and S. Retaux (2010). "Differential expression of LIM-homeodomain factors in Cajal-Retzius cells of primates, rodents, and birds." Cereb Cortex 20(8): 1788-1798.

Aoyama, M., T. Ozaki, H. Inuzuka, D. Tomotsune, J. Hirato, Y. Okamoto, H. Tokita, M. Ohira and A. Nakagawara (2005). "LMO3 interacts with neuronal transcription factor, HEN2, and acts as an oncogene in neuroblastoma." Cancer Res 65(11): 4587-4597.

Aubert, J., M. P. Stavridis, S. Tweedie, M. O'Reilly, K. Vierlinger, M. Li, P. Ghazal, T. Pratt, J. O. Mason, D. Roy and A. Smith (2003). "Screening for mammalian neural genes via fluorescence-activated cell sorter purification of neural precursors from Sox1-gfp knock-in mice." Proc Natl Acad Sci U S A 100 Suppl 1: 11836-11841.

Avraham, O., Y. Hadas, L. Vald, S. Zisman, A. Schejter, A. Visel and A. Klar (2009). "Transcriptional control of axonal guidance and sorting in dorsal interneurons by the Lim-HD proteins Lhx9 and Lhx1." Neural Dev 4: 21.

Bachy, I., P. Vernier and S. Retaux (2001). "The LIM-homeodomain gene family in the developing Xenopus brain: conservation and divergences with the mouse related to the evolution of the forebrain." J Neurosci 21(19): 7620-7629.