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SCIENCE CHINA Function of FEZF1 During Early Neural Differentiation Of SCIENCE CHINA Life Sciences • RESEARCH PAPER • doi: 10.1007/s11427-017-9155-4 Function of FEZF1 during early neural differentiation of human embryonic stem cells Xin Liu1,2, Pei Su1,2, Lisha Lu1,2, Zicen Feng1,2, Hongtao Wang1,2* & Jiaxi Zhou1,2* 1State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China; 2Center for Stem Cell Medicine, Chinese Academy of Medical Sciences & Department of Stem Cells and Regenerative Medicine, Peking Union Medical College, Tianjin 300000, China Received September 13, 2017; accepted November 19, 2017; published online January 2, 2018 The understanding of the mechanism underlying human neural development has been hampered due to lack of a cellular system and complicated ethical issues. Human embryonic stem cells (hESCs) provide an invaluable model for dissecting human development because of unlimited self-renewal and the capacity to differentiate into nearly all cell types in the human body. In this study, using a chemical defined neural induction protocol and molecular profiling, we identified Fez family zinc finger 1(FEZF1)asa potential regulator of early human neural development. FEZF1 is rapidly up-regulated during neural differentiation in hESCs and expressed before PAX6, a well-established marker of early human neural induction. We generated FEZF1-knockout H1 hESC lines using CRISPR-CAS9 technology and found that depletion of FEZF1 abrogates neural differentiation of hESCs. Moreover, loss of FEZF1 impairs the pluripotency exit of hESCs during neural specification, which partially explains the neural induction defect caused by FEZF1 deletion. However, enforced expression of FEZF1 itself fails to drive neural differentiation in hESCs, suggesting that FEZF1 is necessary but not sufficient for neural differentiation from hESCs. Taken together, our findings identify one of the earliest regulators expressed upon neural induction and provide insight into early neural development in human. FEZF1, hESCs, CRISPR/Cas9, neural differentiation Citation: Liu, X., Su, P., Lu, L., Feng, Z., Wang, H., and Zhou, J. (2018). Function of FEZF1 during early neural differentiation of human embryonic stem cells . Sci China Life Sci 61, 1–11. doi: 10.1007/s11427-017-9155-4 INTRODUCTION 2009). They therefore offer an invaluable research tool and unprecedented opportunities for studying human neural lin- Lack of a cellular system and complicated ethical issues have eage specification. To date, many procedures deriving neu- hampered the understanding of the molecular basis of human ral progenitor cell and functional neurons from hPSCs under neural development. Human pluripotent stem cells (hPSCs), chemically defined culture conditions in vitro have been re- including human embryonic stem cells (hESCs) and human ported (Lu et al., 2016; Yao et al., 2006; Zhang et al., 2016; induced pluripotent stem cells (hiPSCs), can be capable of Zhou et al., 2010). Using these neural induction methods, the unlimited proliferation and differentiate into all three embry- molecular mechanisms controlling early human neural differ- onic germ layers in vitro (Thomson et al., 1998; Yamanaka, entiation have begun to be unearthed. The neural commitment from hPSCs is controlled by the *Corresponding authors (Hongtao Wang, email: [email protected]; Jiaxi interplay between extrinsic signaling factors and intrinsic Zhou, email: [email protected]) transcription factors. The extrinsic growth factors regulating © Science China Press and Springer-Verlag GmbH Germany 2018 life.scichina.com link.springer.com 2 Liu, X., et al. Sci China Life Sci neural induction from hPSCs have been well studied. Ac- hESCs were cultured to confluency in mTeSR medium and tivin/Nodal signaling is critical for pluripotency maintenance subsequently differentiated the cells in DMEM/F12 medium and endoderm induction (D’Amour et al., 2005; Vallier et containing KSR and compound C, which induces high-effi- al., 2005), while BMP signaling drives mesendoderm or ciency neural conversion by blocking both the Activin and the trophoectoderm differentiation (Chadwick et al., 2003). The BMP signaling pathway in hESCs. To identify novel essen- inhibition of either Activin/Nodal signaling, BMP signaling, tial regulators during this neural induction process, we used or both has been reported to promote neural differentiation this method to induce neural differentiation from hESCs and (Chambers et al., 2009; Pera et al., 2004; Smith et al., 2008). performed molecular profiling to progenitor cells through- FGF signaling inhibits neural conversion through suppress- out the differentiation time course during the early stages of ing the exit from hPSCs self-renewal (Vallier et al., 2005). neural induction. After 3 days of differentiation, 24 genes Retinoic acid signaling, involved in neural development in were found up-regulated by more than 1.5 folds (Figure 1A Xenopus and mice, induces neural induction and patterning and Table 1). Several previously reported genes critical for in hPSCs (Gamse and Sive, 2000; Niederreither et al., 2000). neural development such as ARHGAP15, FLRT3, ROR2 and WNT signaling plays an important role in specifying regional MEIS2 were included, thereby validating our screening strat- identity of hPSC-derived neural progenitor cells (Moya et al., egy (Agoston et al., 2014; Paganoni et al., 2010; Robinson 2014). In contrast to the understanding of extrinsic signaling et al., 2004; Zamboni et al., 2016). In these genes, FEZF1 factors that control early human neural differentiation, the draw our attention due to its previously documented roles in intrinsic transcription factors driving neural induction from neural development in animals (Eckler et al., 2011; Hirata et hPSCs are still poorly defined. It has been suggested that al., 2006; Shimizu et al., 2010; Watanabe et al., 2009). Using PAX6, OTX2, and SOX2 play an important role in neural real-time PCR and Western blot, we confirmed the up-regu- specificaiton from hPSCs and could be used as early neural lation of FEZF1 during hESC early neural differentiation, ac- differentiation markers (Greber et al., 2011; Zhang and Cui, companied by the increase of neural progenitor specific mark- 2014; Zhang et al., 2010). ers (PAX6, OTX2 and SOX2) and the decrease of pluripo- FEZF1 (Fez family zinc finger 1) belongs to the forebrain tency-associated markers (OCT-4 and NANOG) (Figure 1B embryonic zinc finger (Fez) family and first identified inthe and C). Importantly, the expression of FEZF1 was preceded anterior neuroepitheulim of Xenopus and zebrafish embryos the induction of PAX6, suggesting that FEZF1 may function (Matsuo-Takasaki et al., 2000). During mouse embryogene- as a crucial regulator to hESC neural specification. Given that sis, Fezf1 is first detectable in the head fold at E7.5, expresses FEZF2 play vital roles in mouse neural development (Chen et in the forebrain at E8.5 and exhibits expression in olfactory al., 2008; Guo et al., 2013; McKenna et al., 2011), we also ex- system at E10.5. At E15.5, Fezf1 is broadly expressed in pro- amined the expression pattern of FEZF2 during hESC neural genitor cells and neurons of main olfactory epithelium and induction. Compared with the significant increase of FEZF1 shows expression in the developing amygdala and hypothal- expression, FEZF2 only showed a moderate increase after amus. Genetic loss-of-function studies indicate that Fezf1 is 4 days of differentiation, indicating that FEZF1 may play a implicated in forebrain neurogenesis, olfactory system devel- more important role than FEZF2 in hESC neural commitment opment and patterning of the diencephalon, suggesting the es- (Figure 1B and C). Together, these results pointed to FEZF1 sential role of Fezf1 in mouse neural development (Eckler et as a potential regulator of early human neural differentiation. al., 2011; Hirata et al., 2006; Shimizu et al., 2010; Watanabe et al., 2009). However, the role of FEZF1 in human early FEZF1 silencing impairs neural differentiation of hESCs neurogenesis is still undefined. To assess the role of FEZF1 during neural induction, we In this study, using a chemical defined human neural in- stably silenced endogenous FEZF1 expression in H1 and duction model and molecular profiling we identified FEZF1 H9 cells with shFEZF1-expressing lentiviral vectors. The as a potential regulator of human early neurogenesis. FEZF1 expression level of FEZF1 was significantly decreased knock-down or knock-out impaired hESC early neural differ- in shFEZF1-expressing H1 and H9 cells, as revealed by entiation. Our results indicate FEZF1 is a key transcription real-time PCR and Western blot (Figure 2A and B). After 5 factor in hESC neural commitment, providing insight into the days of neural differentiation, shFEZF1-expressing H1 and endogenous regulation of human neural development. H9 cells exhibited a significant reduction in neural mark- ers (PAX6, OTX2 and SOX2) compared with the control, RESULTS suggesting FEZF1 knockdown impaired neural induction of hESCs (Figure 2C and D). Because the exit of pluripotency FEZF1 identified as an essential regulator of hESC early is required for neural lineage commitment of hESCs, we neural differentiation subsequently detected the effect of FEZF1 silencing on We recently developed a single-step method for neural in- pluripotency exit during neural differentiation of hESCs. As duction of hESCs in adherent cultures (Zhou et al., 2010).
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