Description of Research Expertise:
Early vertebrate development and pattern formation, Wnt signaling, chromatin and epigenetic regulation of early development, hematopoietic stem cell biology, neural stem cells and neurogenesis, neuropharmacology of bipolar disorder, lithium and glycogen synthase kinase-3 (GSK-3).
Key words: Wnt, embryo, signaling, signal transduction, developmental biology, lithium, chromatin, epigenetic, hematopoiesis, stem cell, GSK-3, mTOR, behavior, affective disorders.
Description of Research
This lab studies patterning in early vertebrate development, the regulation of stem cell self-renewal in the hematopoietic system, adult neurogenesis, Wnt signaling, and the molecular mechanisms in the pathogenesis and treatment of neuropsychiatric disorders. Areas of current research include:
1) Wnt signaling modifies chromatin architecture to control early development: We have found that Wnt signaling through ß-catenin establishes poised chromatin architecture at Wnt target promoters in the early embryo. We have identified Prmt2 as a histone H3 arginine-8 methyltransferase and shown that it is recruited by ß-catenin to Wnt target gene promoters and is required for dorsal-ventral patterning. We are currently examining the requirement for Prmt2 in other Wnt-regulated contexts in development and in somatic stem cell populations. We are also exploring the regulation of zygotic gene expression before the midblastula transition, focusing on the role of preMBT transcription in germ layer specification. These experiments are being carried out in Xenopus laevis embryos and in mouse hematopoietic stem cells, and involve microinjection, microsurgical procedures, molecular analysis of chromatin structure and gene expression, and biochemical analysis of the Wnt signaling pathway.
2) Wnt and GSK-3 regulation of hematopoietic stem cell (HSC) self-renewal: We are studying the roles of GSK-3 and Wnt signaling in HSC homeostasis in vivo and in primary HSC culture. We are exploring novel ex vivo culture techniques to define the signaling pathways required for and the gene expression profile associated with HSC self-renewal. In collaboration with Wei Tong at CHOP, we are also studying how JAK/STAT signaling interacts with GSK-3 and Wnts to regulate HSC renewal. These experiments are being carried out with mouse and human hematopoietic stem cells, using novel ex vivo culture techniques and stem cell transplantation assays in mice. These experiments also involve flow cytometry and cell sorting, RNA interference, and biochemical analysis of transmembrane signaling pathways. Our long-term interest is to adapt these findings to clinical applications including hematopoietic stem cell transplantation in humans and treatment of bone marrow failure disorders.
3) Neural signaling pathways that mediate the response to mood stabilizing drugs, with a focus on lithium, GSK-3, and Wnt signaling in the adult central nervous system, in order to understand the molecular pathogenesis and pharmacotherapy of bipolar disorder. This laboratory identified GSK-3 as a direct target of lithium, the most widely used and effective treatment for bipolar disorder. We are currently investigating the downstream molecular targets and the neuronal cell populations within the brain that mediate the response to mood stabilizing drugs. For these experiments, we use neural specific gene knockout and transgenic mice, multiple behavioral assays in adult mice, and in vivo analysis of neural stem cell proliferation and differentiation. In collaboration with Celeste Simon, we are examining interaction between hypoxia inducible factors, GSK-3, and the Wnt pathway in regulating neuronal stem/progenitor cells and the potential role of this cell population in mood disorders.
4) Molecular mechanisms of Wnt signaling: We are also investigating the molecular mechanisms of Wnt signaling, with a focus on how GSK-3 activity is regulated by Wnts. We have found that GSK-3 is positively regulated by the tumor suppressor APC. We are exploring the hypothesis that APC regulates multiple targets through the regulation of GSK-3 activity.
1. Molecular analysis of hematopoietic stem cell signaling in vivo and in ex vivo culture.
2. Chromatin modifications in response to Wnt signaling in HSCs.
3. PreMBT regulation of dorsal-ventral patterning and Wnt signaling in Xenopus embryos.
4. Chromatin modifications in response to developmental signals.
5. Signaling through APC and GSK-3 in colon cancers and other neoplastic syndromes.
6. Mechanisms of lithium action in model systems.
Dheeraj Bhavanasi, postdoctoral fellow
Mindy Snitow, postdoctoral fellow
Michelle Nguyen-McCarty, graduate student
Mansi Shinde, graduate student
Kelsey Speer, graduate student (Lemmon and Klein labs)
Melody Esmaeili, graduate student
Rebecca Myers, graduate student
Yuchen Wang, visiting graduate student
Pamela Burgess-Jones, lab manager
Amanda Reichert, research specialist
Jian Huang, visiting scientist
Valvezan AJ, Huang J, Lengner CJ, Pack M: Oncogenic mutations in Adenomatous Polyposis Coli (Apc) activate mechanistic Target of Rapamycin Complex 1 (mTORC1) Disease Models and Mechanisms 7 (1): 63-71,2014.
Huang J, Nguyen-McCarty M, Hexner EO, Danet-Desnoyers G: Maintenance of Hematopoietic Stem Cells through regulation of Wnt and mTOR Pathways Nature Medicine 18 : 1778-1785,2012.
Valvezan AJ, Zhang FS, Diehl JA: Adenomatous Polyposis Coli (APC) regulates multiple signaling pathways by enhancing glycogen synthase kinase-3 (GSK-3) activity Journal of Biological Chemistry 287 : 3823-3832,2012.
Skirkanich J, Luxardi G, Yang J, Kodjabachian L: An essential role for transcription before the MBT in Xenopus laevis. Developmental Biology 357 : 478-491,2011.
O’Brien WT, Huang J, Buccafusca R, Garskof J, Valvezan AJ, Berry GT: Glycogen synthase kinase-3 is essential for β-arrestin-2 complex formation and lithium-sensitive behaviors in mice. Journal of Clinical Investigation 121 : 3756-3762,2011.
Prepatterning embryonic development: tabula scripta? Developmental Cell 21 : 977-978,2011.
Blythe SA, Cha SW, Tadjuidje E, Heasman J: beta-Catenin primes organizer gene expression by recruiting a histone H3 arginine 8 methyltransferase, Prmt2. Developmental Cell 19 (2): 220-231,2010.
Mazumdar J, O'Brien WT, Johnson RS, LaManna JC, Chavez JC, Klein PS: O2 regulates stem cells through Wnt/β-catenin signalling. Nature Cell Biology 12 (10): 1007-13,2010.
Huang J, Zhang Y, Bersenev A, O'Brien WT, Tong W, Emerson SG: Pivotal role for glycogen synthase kinase-3 in hematopoietic stem cell homeostasis in mice. Journal of Clinical Investigation 119 (12): 3519-29,2009.
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