We use Drosophila and mammalian neural stem cells (NSCs) to model neurodevelopmental disorders and brain tumours.
NSCs are crucial for the development, regeneration, and repair of the nervous system. The delicate balance between NSC quiescence and activation is important for adult neurogenesis and NSC maintenance. We and others are establishing Drosophila NSCs as a model system to elucidate the disease mechanisms underlying neurodevelopmental disorders. Currently, we are interested in addressing the following key questions: What are the intrinsic mechanisms underlying NSC reactivation? What are the molecular signatures of quiescent NSCs? What are the extrinsic signals “waking up” quiescent NSCs?
We and others have established Drosophila larval brain neural stem cells as a model for stem cell self-renewal and tumorigenesis. Our work demonstrated a causal link between deficits in NSC asymmetric division and the formation of brain tumours in Drosophila models. Currently, we are interested in addressing the following key questions: What mutations trigger neural stem cells to become cancer stem cells? How asymmetric divisions of neural stem cells are regulated? What are the mechanisms that prevent more mature cells from dedifferentiating back into neural stem cells?
Prof Wang is an elected EMBO Associate Member (2020), recipient of the Singapore National Academy of Science Young Scientist Award (2008), and the National Research Foundation (NRF) Research Fellowship (2009-2014). She is Associate Editor of PLOS Genetics and Genetics; Asia-Pacific Drosophila Board member, co-chair of Singapore Rare Disease Models and Mechanisms (RDMM), the founding president of Society of Developmental Biologists Singapore, and Vice-President of Stem Cell Society Singapore.
Follow on Twitter: @HongyanWang9
Lin K-Y, Gujar MR, Lin J, Ding WY, Huang J, Gao Y, Tan YS, Teng X, Low SL Christine, Kanchanawong P, Toyama Y, Hongyan Wang. Astrocytes control quiescent NSC reactivation via GPCR signaling-mediated F-actin remodeling. Science Advances (in press)
BioRxiv 2024 https://www.biorxiv.org/content/10.1101/2024.03.11.584337v1
Gujar MR, Gao Y, Teng X, Deng Q, Lin KY, Tan YS, Toyama Y, and Hongyan Wang. Golgi-dependent Reactivation and Regeneration of Quiescent Neural Stem Cells. Developmental Cell (2023) Oct 9;58(19):1933-1949.e5. doi: 10.1016/j.devcel.2023.07.010.
https://www.cell.com/action/showPdf?pii=S1534-5807%2823%2900356-8
BioRxiv 2022 https://www.biorxiv.org/content/10.1101/2022.08.22.504877v1
Gujar MR, Gao Y, Teng X, Ding WY, Lin J, Tan YS, Chew LY, Toyama Y, Hongyan Wang. Patronin/CAMSAP promotes reactivation and regeneration of Drosophila quiescent neural stem cells. EMBO Reports (2023) 13 July
https://doi.org/10.15252/embr.202256624
Deng Q, Wang C, Chwee TK, Heinen JP, Tan YS, Li S, Gonzalez C, Sung WK, and Wang H. Parafibromin Governs Cell Polarity and Centrosome Assembly in Drosophila Neural Stem Cells. PLOS Biology (2022) Oct 12;20(10):e3001834. doi: 10.1371/journal.pbio.3001834. eCollection 2022 Oct. (Press release by Duke-NUS)
https://journals.plos.org/plosbiology/article/comments?id=10.1371/journal.pbio.3001834
Deng Q, Tan YS, Chew LY, and Wang H. Msps Governs Acentrosomal Microtubule Assembly and Reactivation of Quiescent Neural Stem Cells. The EMBO Journal (2021) Aug 9;e104549. doi: 10.15252/embj.2020104549.
https://www.embopress.org/doi/full/10.15252/embj.2020104549
Huang J, Gujar MR, Deng Q, Chia SY, Li S, Tan P, Sung W-K, and Wang H. Histone lysine methyltransferase Pr-set7/SETD8 promotes neural stem cell reactivation. (2021) EMBO Reports Feb 10 2021. DOI: 10.15252/embr.202050994 (Press release by Duke-NUS)
https://www.embopress.org/doi/full/10.15252/embr.202050994
Ding W, Huang J, and Wang H. Waking up quiescent neural stem cells: Molecular mechanisms and implications in neurodevelopmental disorders. PLOS Genetics (2020) Apr 23;16(4)
https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1008653
Ly PT, Tan YS, Koe CT, Zhang Y, Xie G, Endow S, Deng WM, Yu F, Wang H. CRL4Mahj E3 ubiquitin ligase promotes neural stem cell reactivation. PLOS Biology (2019) June 6. (Press release by Duke-NUS)
http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000276
Zhang Y, Koe CT, Tan YS, Ho J, Tan P, Yu F, Sung WK, and Wang H. The Integrator Complex Prevents Intermediate Neural Progenitors Dedifferentiation back into Neural Stem Cells. Cell Reports (2019). Apr 23;27(4):987-996.e3. (Press release by Duke-NUS)
https://doi.org/10.1016/j.celrep.2019.03.089
Huang J and Wang H. Hsp83/Hsp90 physically associates with Insulin Receptor to promote neural stem cell reactivation. Stem Cell Reports (2018). Oct 9. https://doi.org/10.1016/j.stemcr.2018.08.014
Koe CT, Tan YS, Lönnfors M, Hur SK, Lan Low CSL, Zhang Y, Kanchanawong P, Vytas A. Bankaitis VA, Wang H. Vibrator and PI4KIIIa Govern Neuroblast Polarity by Anchoring Non-muscle Myosin II. eLife (2018). Feb 27;7. (Press release by Duke-NUS)
https://elifesciences.org/articles/33555
Li S, Koe CT, Tay ST, Tan ALL, Zhang S, Zhang Y, Tan P, Sung WK and Wang H. An Intrinsic Mechanism Controls Reactivation of Neural Stem Cells by Spindle Matrix Proteins. Nature Communications (2017). Jul 25;8(1):122. (Press release by Duke-NUS). https://www.nature.com/articles/s41467-017-00172-9
Zhang Y, Rai M, Wang C, Cayetano Gonzalez and Wang H. Prefoldin and Pins synergistically regulate asymmetric division and suppress dedifferentiation. Scientific Reports (2016). March 30. https://www.nature.com/articles/srep23735
Chen K, Koe CT, Xing Z, Tian X, Rossi F, Wang C, Tang Q, Zong W, Hong WJ, Taneja R, Yu F, Gonzalez C, Wu C, Endow S, and Wang H. Arl2 and Msps-dependent microtubule growth governs asymmetric division. Journal of Cell Biology (2016). March 14; 212 (6).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4792071/
Angeles DC, Ho P, Chua LL, Wang C, Yap YW, Ng C, Zhou ZD, Lim KL, Wszolek ZK, Wang H, and Tan EK. Thiol-peroxidases ameliorate LRRK2 mutant-induced mitochondrial and dopaminergic neuronal degeneration in Drosophila. Human Molecular Genetics (2014) June 15; 23:3157-65.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030771/
CT Koe, S Li, F. Rossi, JJL Wong, Y Wang, Z Zhang, K. Chen, S. Aw, HE Richardson, P Robson, WK Sung, F Yu, C Gonzalez, and Hongyan Wang. The Brm-HDAC3-Erm repressor complex suppresses dedifferentiation in Drosophila type II neuroblast lineages. eLife (2014) March 11. (Press release by Duke-NUS). https://elifesciences.org/articles/01906
Song Li, Cheng Wang, Edwin Sandanaraj, Sherry S.Y. Aw, Chwee Tat Koe, Jack J. L. Wong, Fengwei Yu, Beng Ti Ang, Carol Tang, and Hongyan Wang. The SCFSlimb E3 ligase complex regulates asymmetric division to inhibit neuroblast overgrowth. EMBO Reports (2014) 15, 165-174. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3989862/
Wang C, Li S, Januschke J, Rossi F, Izumi Y, Garcia-Alvarez G, Gwee SL, Soon SB, Sidhu HK, Yu F, Matsuzaki F, Gonzalez C, and Wang H. An Ana2/Ctp/Mud complex regulates spindle orientation in Drosophila neuroblasts. (2011). Developmental Cell, 21, 520-33. https://www.cell.com/action/showPdf?pii=S1534-5807%2811%2900314-5
Chang KC, Garcia-Alvarez G, Somers G, Sousa-Nunes R, Rossi F, Lee YY, Soon SB, Gonzalez C, Chia W and Wang H. Interplay between the transcription factor Zif and aPKC regulates neuroblast polarity and self-renewal. (2010). Developmental Cell, 19, 778-85. (Press release by Development Cell, Duke University and Duke-NUS). https://www.cell.com/action/showPdf?pii=S1534-5807%2810%2900460-0
Wang C., Chang KC, Somers GW, Virshup D, Ang BT, Tang C, Yu F and Wang H. Protein Phosphatase 2A regulates self-renewal of Drosophila neural stem cells. (2009) Development 136, 2287-96. (Press released by Development, Duke University and Duke-NUS) http://dev.biologists.org/content/136/13/2287.long
Wang H, Ouyang Y, Somers GW, Chia W and Lu B. Polo inhibits neural progenitor self-renewal and regulates Numb asymmetry by phosphorylating Pon. Nature 449, 96-100 (2007) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3047501/
Wang H, Somers GW, Bashirullah A, Heberlein U, Yu F and Chia W. Aurora-A acts as a tumor suppressor and regulates self-renewal of Drosophila neuroblasts. Genes and Development 20:3453-63 (2006). (Press released by Cold Spring Harbor Laboratory Press)
http://genesdev.cshlp.org/content/20/24/3453.long
Wang H, Ng KH, Qian H, Siderovski DP, Chia W and Yu F. RIC-8 controls Drosophila neural progenitor asymmetric division by regulating heterotrimeric G proteins. Nature Cell Biology 7:1091-1098 (2005). https://www.nature.com/articles/ncb1317