Dr. Wu-Min Deng
Laboratory Home Page
Ph.D., The University of Edinburgh, UK, 1997
Graduate Faculty Status
Cell signaling, oocyte polarity and Drosophila models for cancer
We are interested in how important cellular decisions such as proliferation, growth and polarization are made during animal development. Dysregulation of these cellular processes are tightly associated with tumorigenesis and cancer formation. My laboratory mainly uses Drosophila as a model organism to study the molecular and cellular mechanisms underlying these cellular behaviors. The current research in my lab has three major foci (described in detail below): (1) temporal regulation of cell proliferation, growth, and differentiation in the follicle cells, (2) the cellular mechanisms the oocyte uses to establish asymmetric maternal-determinant positioning and therefore its polarity, and (3) the molecular mechanisms underlying cell competition in epithelial cells.
Development of a multicellular organism requires regulation of cellular events that are highly orchestrated temporally and spatially. Although much research has been conducted on spatial regulation of cell differentiation and gene expression, relatively little is known about how basic cellular functions are regulated temporally. The follicle cells provide an excellent model system for study of the temporal regulation of cell proliferation and differentiation. In the course of oogenesis, the follicle cells undergo two important switches of cell-cycle program, first from the normal mitotic cell cycle to the specialized endocycle (in which cells duplicate their genomic DNA without dividing) and second from the endocycle to amplification of specific genomic regions. These switches are essential for supporting egg development and are coupled with other temporally and spatially regulated changes of differentiation and growth status. For example, at the first switch, follicle cells stop proliferation, grow in size, and begin expressing different fate markers. Spatially, these cells undergo different movements to reach their final destination. My lab has played a major role in identifying how expression of specific genes contributes to specific types of follicle-cell behavior. Our work has led to a much greater understanding of the temporal and spatial patterns of the follicle cells.
Our work revealed that the evolutionarily conserved Notch pathway has a unique and crucial role in temporal regulation of follicle-cell differentiation and proliferation. Notch signaling is activated by the germ-cell-expressed ligand Delta, which triggers the first of the two cell-cycle switches mentioned above. Several recent studies in my lab reveal that two transcription factor genes, hindsight and cut, are affected by Notch signaling during this first switch. Notch signaling turns on hindsight activity, which inhibits follicle cell proliferation by suppressing both cut and a proliferation-stimulating signaling pathway. Our studies established cut and hindsight as key linkers to connect Notch signaling and the cell-cycle machinery. More recently, we found that the precise timing of Notch activation is regulated by the microRNA pathway. We are currently in the process of determining how microRNAs Notch signalling and developmental timing in follicle cells.
Turning off a signaling system can be as important as turning it on. Recently, we found that turning off Notch signaling as well as activation of ecdysone receptor pathway are required for the second of the two switches. Our study was the first to show how developmental signals control the second switch in the Drosophila follicular system. It also has much wider significance in that it is among the few that demonstrate important developmental consequences after a signaling pathway is turned off in cells. Interestingly, we found that a microRNA, miR-7, plays a critical role in regulating this endocycle to gene amplification switch.
In addition, we found that Notch activation in follicle cells is spatially regulated by a tumor-suppressor pathway, the Hippo pathway. When this pathway is disrupted, Notch is strongly compromised in the posterior follicle cells, which are particularly important for sending signals to the oocyte that help establish its asymmetry. We also identified a novel bona fide component of the Hippo pathway, KIBRA. Precisely how Hippo and Notch signaling intertwine in the follicle cells is of great interest to us. We have some preliminary data showing the trafficking of Notch is compromised in Hippo pathway mutants. Further study on this topic will help us decipher the interaction of these two important and conserved pathways.
During Drosophila oogenesis, the germline cells and the somatic follicle cells interact constantly, sending signals back and forth to communicate and eventually to build a functional egg for the development of the next generation. These oocytes are asymmetrically constructed, storing positional information, specific mRNAs and proteins that are localized in specific subcellular compartments. When the egg is fertilized, these localized molecules direct the formation of the major body axes—the anterior-posterior (AP) and the dorsal-ventral (DV) axes—a process fundamental to the development of bilateral animals. The localization of these determinants requires the oocyte to build a polarized network of cytoskeleton microtubules. Although many players involved in this polarity formation have been identified, several key steps in the process remain unclear. For example, posterior follicle cells were known to signal a change in oocyte polarity, but the nature of signal remained unknown.
My lab has investigated both the nature of the posterior follicle cell signaling and the responding mechanisms working in the oocyte to establish the proper polarity. We have shown that a follicle-cell extracellular-matrix component is required for proper oocyte polarity. Work in my lab led to the discovery that the Epidermal Growth Factor Receptor signaling pathway, as well as Notch signaling, downregulates expression of Dystroglycan (a transmembrane complex that when defective leads to muscular dystrophy in humans) in follicle cells.
Inside the oocyte, how microtubule polarity is regulated is also largely unclear. Recently, we have revealed a novel pathway that involves tumor-suppressor Lethal Giant Larvae (Lgl) and conserved cell-polarity genes such as aPKC and Par-1 to regulate the microtubule asymmetry in the oocyte.
Recently, genetic analyses in Drosophila have revealed various genes that regulate the competitive behavior of cells. Among these, the neoplastic tumor-suppressor genes (nTSGs) have been shown to fulfill two significant functions requisite for organ size control: first, establishing apicobasal cell polarity as a principle of epithelial tissue organization and appropriate timing of terminal differentiation and, second, exerting cell-proliferation control as a primary factor in tissue growth. Our recent studies revealed that nTSG Lgl and its novel binding partner Mahjong (Mahj) are involved in cell competition. In the mosaic Drosophila wing imaginal discs, mahj-/- or lgl-/- cells adjacent to wild-type cells undergo apoptosis, whereas mahj-/- or lgl-/- cells that are not adjacent to wild-type cells do not. The nonautonomous apoptosis in these mutant cells is suppressed by inhibition of the JNK pathway. Furthermore, overexpression of Mahj in lgl-/- mutant cells suppresses JNK activation and blocks apoptosis of lgl-/- mutant cells in the wild-type wing-disc epithelium. In collaboration with Dr Fujita at University College London, we found that Mahj-knockdown mammalian MDCK cells were also eliminated by wildtype cells through cell competition. Taken together, our data suggest that Mahjong and Lgl belong to a molecular pathway that plays an evolutionarily conserved role in regulating cellular competitiveness.
In summary, the three major areas of research in my lab are independent yet connected—proper differentiation of follicle cells is key to the establishment of oocyte polarity, and cell competition involves intercellular communication and regulation of cell proliferation. Through the study of temporal and spatial regulation of important genes and pathways in our model systems, we will develop a more comprehensive picture of the molecular mechanisms orchestrating egg development and gain a deeper understanding of how basic cellular functions such as proliferation, differentiation, and growth are regulated in development.
Jia D, Xu Q, Xie Q, Mio W, Deng WM. (2016) Automatic stage identification of Drosophila egg chamber based on DAPI images. Sci Rep. 6: 18850.
Palmer WH, Deng WM. (2015) Ligand-Independent Mechanisms of Notch Activity. Trends Cell Biol. 25(11): 697-707.
Jia D, Huang YC, Deng WM. (2015) Analysis of Cell Cycle Switches in Drosophila Oogenesis. Methods Mol Biol. 1328: 207-16.
Jia D, Soylemez M, Calvin G, Bornmann R, Bryant J, Hanna C, Huang YC, Deng WM. (2015) A large-scale in vivo RNAi screen to identify genes involved in Notch-mediated follicle cell differentiation and cell cycle switches. Sci Rep. 5:12328.Zhang H, Li C, Chen H, Wei C, Dai F, Wu H, Dui W, Deng WM, Jiao R. (2015) SCF(Slmb) E3 ligase-mediated degradation of Expanded is inhibited by the Hippo pathway in Drosophila. Cell Res. 25: 93-109.
Yu Z, Liu J, Deng WM, Jiao R. (2015) Histone chaperone CAF-1: essential roles in multi-cellular organism development. Cell Mol Life Sci. 72(2):327-37.
Yu Z, Chen H, Liu J, Zhang H, Yan Y, Zhu N, Guo Y, Yang B, Chang Y, Dai F, Liang X, Chen Y, Shen Y, Deng WM, Chen J, Zhang B, Li C, Jiao R. (2014).Various applications of TALEN- and CRISPR/Cas9-mediated homologous recombination to modify the Drosophila genome. Biol Open. 3(4):271-80. doi: 10.1242/bio.20147682.
Palmer WH, Jia D, Deng WM. (2014) Cis-interactions between Notch and its ligands block ligand-independent Notch activity. Elife. 3. doi: 10.7554/eLife.04415. Xie G, Yu Z, Jia D, Jiao R, Deng WM. (2014). E(y)1/TAF9 mediates the transcriptional output of Notch signaling in Drosophila. J Cell Sci. 127:3830-9.
Jia D, Tamori Y, Pyrowolakis G, Deng WM. (2014). Regulation of broad by the Notch pathway affects timing of follicle cell development. Dev Biol. 392:52-61.
Tamori, Y., & Deng, W.-M. (2014). Compensatory cellular hypertrophy: the other strategy for tissue homeostasis. (Invited review), 24:230-7.
Klusza, S., Novak, A., Figueroa, S., Palmer, W., & Deng, W.-M. (2013). Prp22 and spliceosome components regulate chromatin dynamics in germ-line polyploid cells. Plos One, 8, e79048.
Yu, Z., Wu, H., Chen, H., Wang, R., Liang, X., Liu, J., Li, X., Deng, W.-M., & Jiao, R. (2013). CAF-1 promotes Notch signaling through epigenetic control of target gene expression during Drosophila development. Development, 140, 3635-44.
Tamori, Y., & Deng, W.-M. (2013). Tissue repair through cell competition and compensatory cellular hypertrophy in postmitotic epithelia. Developmental Cell, 25, 350-363.
Huang, Y. C., Smith, L., Poulton, J., & Deng, W.-M. (2013). The microRNA miR-7 regulates Tramtrack69 in a developmental switch in Drosophila follicle cells. Development, 140, 897-905.
Tian, A. G., Tamori, Y., Huang, Y. C., Toledo Melendez, N., & Deng, W.-M. (2013). Efficient EGFR signaling and dorsal-ventral axis patterning requires syntaxin dependent Gurken trafficking. Dev. Biol, 373, 349-358.
Heck, B. W., Zhang, B., Tong, X., Deng, W.-M., & Tsai, C. C. (2012). The transcriptional corepressor SMRTER influences both Notch and ecdysone signaling during Drosophila development. Biol Open. 1, 182-196.
Liu, J., Li, C., Huang, P., Wu, H., Wei, C., Zhu, N., Shen, Y., Chen, Y., Deng, W.-M., & Jiao, R. (2012). Efficient and specific modifications of the Drosophila genome by means of an easy TALEN strategy. J Genet Genomics, 39, 209-215.
Tamori Y, Deng WM. 2011. Cell competition and its implications for development and cancer. J Genet Genomics. 38(10):483-95.
Deng WM. 2011. Molecular genetics of cancer and tumorigenesis: Drosophila models. J Genet Genomics. 38(10):429-30
Poulton J, Huang YC, Smith L, Sun JJ, Leake N, Schleede J, Stevens L, Deng WM. 2011. The microRNA pathway regulates the temporal pattern of Notch signaling in Drosophila follicle cells. Development. 138(9):1737-45.
Klusza S, Deng WM. 2011. At the crossroads of differentiation and proliferation: Precise control of cell-cycle changes by multiple signaling pathways in Drosophila follicle cells Bioessays. 33(2):124-34.
Yoichiro T, Bialucha CU, Tian AG, Kajita M, Huang YC, Norman M, Harrison N, Poulton J, Ivanovitch K, Disch L, Liu T, Deng WM*, Fujita Y*. 2010. Involvement of Lgl and Mahjong/VprBP in Cell Competition PLoS Biology. doi:10.1371/journal.pbio.1000422 (*Deng and Fujita are equal contributing co-corresponding authors). (#18 in Discover magazine top 100 Stories of 2010)
Klusza S, Deng WM. 2010. poly is required for nurse-cell chromosome dispersal and oocyte polarity in Drosophila Fly (Austin). 4(2):128-36.
Yu J, Zheng Y, Dong J, Klusza S, Deng WM *, Pan D *. 2010. Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. Developmental Cell. 18(2):288-99. (*Deng and Pan are equal contributing co-corresponding authors)
Shyu LF, Sun J, Chung HM, Huang YC, Deng WM. 2009. Notch signaling and developmental cell-cycle arrest in Drosophila polar follicle cells. Molecular Biology of the Cell 20(24):5064-73.
Yatsenko AS, Kucherenko MM, Pantoja M, Fischer KA, Madeoy J, Deng WM, Schneider M, Baumgartner S, Akey J, Shcherbata HR, Ruohola-Baker H. 2009. The conserved WW-domain binding sites in Dystroglycan C-terminus are essential but partially redundant for Dystroglycan function. BMC Developmental Biology. 27:9-18
Tian AG, Deng WM. 2009. Par-1 and Tau regulate the anterior-posterior gradient of microtubules in Drosophila oocytes Developmental Biology. 327(2):458-64.
Cooper E, Deng WM, Chung HM. 2009. Aph-1 is required to regulate Presenilin-mediated gamma-secretase activity and cell survival in Drosophila wing development Genesis. 47(3):169-74.
Sun J, Smith L, Armento A, Deng WM. 2008. Regulation of the endocycle/gene amplification switch by Notch and ecdysone signaling The Journal of Cell Biology. 182(5):885-96.
Yu J, Poulton J, Huang YC, Deng WM. 2008. The Hippo Pathway Promotes Notch Signaling in Regulation of Cell Differentiation, Proliferation, and Oocyte Polarity PLoS ONE. 3(3): e1761.
Tian AG, Deng WM. 2008. Lgl and its phosphorylation by aPKC regulate oocyte polarity formation in Drosophila Development. 135(3):463-71.
Poulton J, Deng WM. 2007. Cell-cell communication and axis specification in the Drosophila oocyte. Developmental Biology. 311(1):1-10.
Sun J, Deng WM. 2007. Hindsight mediates the role of notch in suppressing hedgehog signaling and cell proliferation Developmental Cell. 12(3):431-42.
Schneider M, Khalil AA, Poulton J, Castillejo-Lopez C, Egger-Adam D, Wodarz A, Deng WM, Baumgartner S. 2006. Perlecan and Dystroglycan act at the basal side of the Drosophila follicular epithelium to maintain epithelial organization Development. 133: 3805-15.
Poulton JS., Deng WM. 2006. Dystroglycan down-regulation links EGF receptor signaling and anterior-posterior polarity formation in the Drosophila oocyte Proc Natl Acad Sci U S A. 103(34): 12775-80.
Sun J, Deng WM. 2005. Notch-dependent downregulation of the homeodomain gene cut is required for the mitotic cycle/endocycle switch and cell differentiation in Drosophila follicle cells Development 132: 4299-4308.
Althauser C, Jordan K, Deng WM, Ruohola-Baker H. 2005. Fringe-dependent notch activation and tramtrack function are required for specification of the polar cells in Drosophila oogenesis Developmental Dynamics 232: 1013-1020.
Schaeffer V., Althauser C., Shcherbata HR, Deng WM, Ruohola-Baker H. 2004. Notch-dependent Fizzy-related/Hec1/Cdh1 expression is required for the mitotic-to-endocycle transtition in Drosophila follicle cells Current Biology 14(7): 630-6.
Deng, W.M., M. Schneider, R.W. Frock, C. Castillejo-Lopez, S. Baumgartner, and H. Ruohola-Baker. 2003. Dystroglycan is required for polarizing the epithelial cells and the oocyte in Drosophila Development 130: 173-184. (COVER PHOTOGRAPH).
Deng, W.M., C. Althauser, and H. Ruohola-Baker. 2001. Notch-Delta signaling induces a transition from mitotic cell cycle to endocycle in Drosophila follicle cells Development 128: 4737-4746. (COVER PHOTOGRAPH).
Deng, W.M., and H. Ruohola-Baker. 2000. Laminin A is required for follicle cell-oocyte signaling that leads to establishment of the anterior-posterior axis in Drosophila Current Biology 10: 683-686.
Jordan, K.C., N.J.Clegg, J.A. Blasi, A.M. Morimoto, J.Sen, D.Stein, H.McNeill, W.M. Deng, M. Tworoger, and H. Ruohola-Baker. 2000. The homeobox gene mirror links EGF signaling to embryonic dorso-ventral axis formation through notch activation. Nature Genetics 24: 429-433.
Larkin, M.K.,* W.M. Deng,* K. Holder, M. Tworoger, N. Clegg, and H. Ruohola-Baker. 1999. Role of Notch pathway in terminal follicle cell differentiation during Drosophila oogenesis. Development Genes & Evolution 209: 301-311. (*equal contribution)
Deng, W.M., K. Leaper, and M. Bownes. 1999. A targeted gene silencing technique show that Drosophila myosin VI is required for egg chamber and imaginal disc morphogenesis Journal of Cell Science 112: 3677-3690.
Tzolovsky, G.,* W.M. Deng,* T. Schlitt, and M. Bownes. 1999. The Function of the broad complex during Drosophila melanogaster oogenesis. Genetics 153: 1371-1383. (*equal contribution)
Hicks, J.L., W.M. Deng, A.D. Rogat, K.G. Miller, and M. Bownes. 1999. Class VI unconventional myosin is required for spermatogenesis in Drosophila Molecular Biology of the Cell 10: 4341-4353.
Deng, W.M., and M. Bownes. 1998. Patterning and morphogenesis of the follicle cell epithelium during Drosophila oogenesis. : 441-552.
Deng, W.M., and M. Bownes. 1997. Two signaling pathways specify localised expression of the broad complex in Drosophila eggshell patterning and morphogenesis. Development 124: 4639-4647.
Deng, W.M., D. Zhao, K. Rothwell, and M. Bownes. 1997. Analysis of P[gal4] insertion lines of Drosophila melanogaster as a route to identifying genes important in the follicle cells during oogenesis. Molecular Human Reproduction 5: 101-110.
Deng, W.M., and D. Zhao. 1994. Multiple expressions and functions of developmental regulatory genes. Chinese Journal of Cell Biology 14: 164-171.Postdoctoral Associates: