Xin Liu, M.D., Ph.D.
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Work Phone Number:
CAMPUS - 173216
|Director, Embryonic Stem Cells|
|Associate Professor, Molecular & Medical Pharmacology|
|Assistant Professor, Pathology and Laboratory Medicine|
|Member, Brain Research Institute, JCCC Cancer and Stem Cell Biology Program Area, Molecular Biology Institute, Neuroengineering Training Program|
|Faculty, Cellular and Molecular Pathology PhD Program|
Neurotrophins (NTs) study has had 56 years of history and is the largest field in neuroscience. In the center of this study is neurotrophinsÃÂ function in neuronal survival. For many years, this question is not clear because neurotrophins have four genes and may compensate for each other. By knocking out three of the four neurotrophin genes, we showed that NTs control the survival of most, if not all, of the peripheral nervous system (PNS) sensory neurons and a small portion (~20%) of motor neurons during embryogenesis (Liu and Jaenisch, 2000). In addition to neurotrophin survival study, we are interested in neurotrophinsÃÂ novel function. Recently, the role of NTs in regulating neuronal plasticity has been indicated. We examined NT4 mutant mice and discovered that NT4 mutants have deficits in long-term memory and hippocampal long-lasting long-term potentiation (L-LTP) but not learning, short-term memory, and decremental LTP (Xie et al., 2000). Another new role of NTs is in the tolerance to substances of abuse. Tolerance is an important component of opiate addiction, but the molecular basis for this phenomenon remains obscure. Recently, we reported that mice lacking NT4 display substantially reduced tolerance to morphine compared to wild-type. However, there are no deficits in sensitization, withdrawal, and other behaviors relevant to drug addiction (Smith et al., 2003). Since NT4 knockout mice also show abnormalities in long-term but not short-term memory, our findings suggest common molecular pathways for some of the enduring changes of drug addiction and memory consolidation.
The Delta-catenin (d-cat), a novel member of the Armadillo protein family, is exclusively expressed in the brain and interacts with Presenilin-1 (PS1). Mutations in PS1 are responsible for more than 70% of familial AlzheimerÃÂs disease (FAD). The d-cat also interacts with cadherins, which is a component of adherens junction that is essential for the integrity of synapses. Synapse is key for learning and memory and a primary target of onset of AlzheimerÃÂs disease (AD). We knocked out d-cat and found that d-cat is an important molecule in synaptic plasticity (Israely, el.al., 2003, in preparation). Our behavioral study showed that the learning and memory, but not the motor ability, of mutant mice are severely impaired. Using standard water maze test, we found that both wild-type and mutant mice can locate the visible platform above water. However, only wild-type mice, but not mutant mice, can locate the platform in submerged water. In extinctive fear conditioning test, we found that mutants have a significant deficit in learning. Our electrophysiological study showed that our mutant mice have enhanced LTP. Recently, we focus on the molecular mechanisms of d-cat.
The tumor suppressor, PTEN (phosphatase and tensin homolog deleted from chromosome 10), is a tyrosine phosphatase mutated at high frequencies in many primary human cancers. Since itÃÂs cloning in 1997, PTEN has been one of the most intensely studied genes. Using loss-of-function analysis, we found that PTEN regulates the phosphatidylinositol 3-kinase (PI3K) and Akt signaling pathway and consequently modulates two critical cellular processes: cell cycle and cell survival (Sun et al., 1999). To avoid embryonic lethality in order to examine PTEN function in the brain during development and in adults, we made three independent brain-specific PTEN mutant mouse strains. These strains have mutated PTEN in certain tissues of the brain and at particular developmental times. The first strain, nesting/PTEN, has deletion of PTEN during mid-embryonic stage in the brain cortex (day 8.5) and has increased cell proliferation, decreased cell death, and enlarged cell size. The stem/progenitor cells derived from the mutant brain have a greater proliferation capacity and shortened cell cycle. Our results suggest that PTEN negatively regulates neural stem cell proliferation without perturbing its differentiation program (Groszer et al., 2002). This study produced a mouse model of brain tumor. We are testing the synergistic effects of p53 tumor suppressor on PTEN functions and the potential therapeutic benefits of rapamycin on hyperproliferative neural stem cells or brain tumors caused by PTEN loss. The second strain, GFAP/PTEN, has a deletion of PTEN in the brain of late embryonic stage (day 14). Our data showed that deleting PTEN in the Bergmann glia of cerebellum cortex caused a morphological conversion from Bergmann glia to astrocytes and led to an abnormal migration of the granular cell in the cerebellum (Yue et al., 2003, manuscript in preparation). The third strain, CamKII/PTEN, has a deletion of PTEN in the hippocampus and cortex of the brain at adult stage (3 weeks). We discovered that the cortex of this mouse started to grow abnormally from the two and a half month of age. There are strong interests in cancer and repair in the brain cortex. We are investigating whether the number or the size of these cells increases in the cortex and whether there are proliferating stem cells in the adult cortex. In addition to brain-specific PTEN mutant strains, we examined the LTP and behavior of PTEN+/- mice because an increasing number of studies suggest PI3K/Akt signal pathway plays an important role of synapse function. We discovered that rapamycin enhances the sensitivity of early LTP in PTEN +/- mice, suggesting that PTEN regulates learning and memory (Groszer el.al., 2003, manuscript in preparation).
Hideaki Tsutsui*, Bahram Valamehr*, Antreas Hindoyan, Rong Qiao, Xianting Ding, Shuling Guo, Owen N. Witte, Xin Liu, Chih-Ming Ho & Hong Wu. An optimized small molecule inhibitor cocktail supports long-term maintenance of human embryonic stem cells. Nat Commun 2011; 2:167: 1-8.
Goebbels, S., Oltrogge, J., Kemper, R., Heilmann, I., Wichert, S., Bormuth, I., Wolfer, S., Liu, X., Lappe-Siefke, C., Rossner, M., Groszer, M., Suter, U., Frahm, J., Boretius, S., and Nave, K. Elevated phosphatidylinositol 3,4,5 trisphosphate in glia triggers cell autonomous membrane wrapping and myelination. J. Neuroscience 2010; 30(26): 8953-64.
Matter Cheryl, Pribadi Mochtar, Liu Xin, Trachtenberg Joshua T Delta-catenin is required for the maintenance of neural structure and function in mature cortex in vivo. Neuron. 2009; 64(3): 320-7.
Gregorian Caroline, Nakashima Jonathan, Dry Sarah M, Nghiemphu P Leia, Smith Kate Barzan, Ao Yan, Dang Julie, Lawson Gregory, Mellinghoff Ingo K, Mischel Paul S, Phelps Michael, Parada Luis F, Liu Xin, Sofroniew Michael V, Eilber Fritz C, Wu Hong PTEN dosage is essential for neurofibroma development and malignant transformation. Proceedings of the National Academy of Sciences of the United States of America. 2009; 106(46): 19479-84.
Arikkah, J., Peng, F., Ng, Y., Israely, I., Liu, X., Ullian, E., Reichardt, L. Delta-catenin regulates spine and synapse morphogenesis and function in hippocampal neurons. J. Neuroscience 2009; 29(17): 5435-5442.
Valamehr Bahram, Jonas Steven J, Polleux Julien, Qiao Rong, Guo Shuling, Gschweng Eric H, Stiles Bangyan, Kam Korey, Luo Tzy-Jiun M, Witte Owen N, Liu Xin, Dunn Bruce, Wu Hong Hydrophobic surfaces for enhanced differentiation of embryonic stem cell-derived embryoid bodies. Proceedings of the National Academy of Sciences of the United States of America. 2008; 105(38): 14459-64.
Arikkath Jyothi, Israely Inbal, Tao Yanmei, Mei Lin, Liu Xin, Reichardt Louis F Erbin controls dendritic morphogenesis by regulating localization of delta-catenin. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2008; 28(28): 7047-56.
Arikkath, J., Israely, I., Tao, Y., Mei, L., Liu, X., and Reigardt, L Erbin controls dendritic morphogenesis by regulating localization of -catenin. J. Neuroscience 2008; 28(28): 7047-7056.
Freeman Dan, Lesche Ralf, Kertesz Nathalie, Wang Shungyou, Li Gang, Gao Jing, Groszer Matthias, Martinez-Diaz Hilda, Rozengurt Nora, Thomas George, Liu Xin, Wu Hong Genetic background controls tumor development in PTEN-deficient mice. Cancer research. 2006; 66(13): 6492-6.
Li, G., Hu, Y., Huo, Y., Liu, M., Freeman, D., Gao, J., Liu, X., Wu, DC., and Wu, H. PTEN deletion leads to up-regulation of a secreted growth factor pleiotrophin. . J Biol Chem. 2006; 281(16): 10663-8.
Groszer, M., Erickson, R., Scripture-Adams, D., Dougherty, J., LeBelle, J., Zack, J., Geschwind, D., Liu, X., Kornblum, H., Wu, H. PTEN negatively regulates neural stem cell self-renewal by modulating G0-G1 cell cycle entry. Proc. Natl. Acad. Sci. USA 2006; 103: 111-116.
He, XP., Bulter, L., Liu, X., and McNamara, JO. The tyrosine receptor kinase B ligand, neurotrophin-4, is not required for either epileptogenesis or tyrosine receptor kinase B activation in the kindling model. Neuroscience 2006; 141(1): 515-520.
Lei Qunying, Jiao Jing, Xin Li, Chang Chun-Ju, Wang Shunyou, Gao Jing, Gleave Martin E, Witte Owen N, Liu Xin, Wu Hong NKX3.1 stabilizes p53, inhibits AKT activation, and blocks prostate cancer initiation caused by PTEN loss. Cancer cell. 2006; 9(5): 367-78.
Tsai Peter T, Ohab John J, Kertesz Nathalie, Groszer Matthias, Matter Cheryl, Gao Jing, Liu Xin, Wu Hong, Carmichael S Thomas A critical role of erythropoietin receptor in neurogenesis and post-stroke recovery. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2006; 26(4): 1269-74.
Yue Q, Groszer M, Gil JS, Berk AJ, Messing A, Wu H, Liu X PTEN deletion in Bergmann glia leads to premature differentiation and affects laminar organization. Development (Cambridge, England) . 2005; 132(14): 3281-91.
Nakano, I., Paucar, A., Bajpai, R., Dougherty, J., Zewail, A., Kim, K., Ou, J., Groszer, M., Imura, T., Freije, W., Nelson, S., Sofroniew, M., Wu, H., Liu, X., Terskikh, A., Geschwind, D., Kornblum, H. Maternal embryonic leucine zipper kinase (MELK) regulates multipotent neural progenitor proliferation. J. Cell Biol 2005; 170: 413-427.
Kosik KS, Donahue CP, Israely I, Liu X, Ochiishi T Delta-catenin at the synaptic-adherens junction. Trends in cell biology. 2005; 15(3): 172-8.
Israely I, Costa RM, Xie CW, Silva AJ, Kosik K and Liu X The neuronal specific protein Delta-Catenin is essential for cognitive function. . Current Biology 2004; 14 (18): 1657-1663.
Tan M, Groszer M, Tan AM, Pandya A, Liu X, Xie CW Phosphoinositide 3-kinase cascade facilitates mu-opioid desensitization in sensory neurons by altering G-protein-effector interactions. The Journal of neuroscience : the official journal of the Society for Neuroscience. . 2003; 23(32): 10292-301.
Colwell CS, Michel S, Itri J, Rodriguez W, Tam J, Lelievre V, Hu Z, Liu X, Waschek JA Disrupted circadian rhythms in VIP- and PHI-deficient mice. American journal of physiology. Regulatory, integrative and comparative physiology. . 2003; 285(5): R939-49.
Wang S, Gao J, Lei Q, Rozengurt N, Pritchard C, Jiao J, Thomas GV, Li G, Roy-Burman P, Nelson PS, Liu X, Wu H Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer cell. . 2003; 4(3): 209-21.
Smith DJ, Leil TA, Liu X Neurotrophin-4 is required for tolerance to morphine in the mouse. Neuroscience letters. . 2003; 340(2): 103-6.
Li G, Robinson GW, Lesche R, Martinez-Diaz H, Jiang Z, Rozengurt N, Wagner KU, Wu DC, Lane TF, Liu X, Hennighausen L, Wu H Conditional loss of PTEN leads to precocious development and neoplasia in the mammary gland. Development (Cambridge, England) . 2002; 129(17): 4159-70.
Lesche R, Groszer M, Gao J, Wang Y, Messing A, Liu X and Wu H Cre/loxp-Mediated Inactivation of The Murine Pten Tumor Suppressor Gene. Genesis 2002; 32: 148-149.
Stiles B, Gilman V, Khanzenzon N, Lesche R, Li A, Qiao R, Liu X, Wu H Essential role of AKT-1/protein kinase B alpha in PTEN-controlled tumorigenesis. Molecular and cellular biology. . 2002; 22(11): 3842-51.
Groszer M, Erickson R, Scripture-Adams DD, Lesche R, Trumpp A, Zack JA, Kornblum HI, Liu X, Wu H Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science. . 2001; 294(5549): 2186-9.
Xie CW, Sayah D, Chen QS, Wei Wz, Smith D and Liu X Deficient long-term memory and long-term potentiation with a targeted null mutation in neurotrophin-4 gene. Proc. Natl. Acad. Sci. USA 2000; 97: 8116-8121.
Endres M, Fan GP, Hirt L, Fujii M, Liu X, Jaenisch R, Moskowitz MA Ischemic brain damage in mice after selectively modifying BDNF or NT4 gene expression. Journal of Cerebral Blood Flow and Metabolism 2000; 20(1): 139-144.
Liu X, Jaenisch R Severe peripheral sensory neuron loss and modest motor neuron reduction in mice with combined deficiency of brain-derived neurotrophic factor, neurotrophin 3 and neurotrophin 4/5. Developmental dynamics : an official publication of the American Association of Anatomists. . 2000; 218(1): 94-101.
Wu H, Lee SH, Gao J, Liu X, Iruela-Arispe ML Inactivation of erythropoietin leads to defects in cardiac morphogenesis. Development (Cambridge, England) . 1999; 126(16): 3597-605.
Sun H, Lesche R, Li Dm, Liliental J, Zhang H, Gao J, Gavriola N, Mueller B, Liu X, and Wu H PTEN Modulates Cell Cycle Progression and Cell Survival by Regulating Phosphatidylinositol 3,4,5,-Triphophate and Akt/Protein Kinase B Signaling Pathway. PNAS 1999; 96: 6199-6204.
Liu X, Wu H, Loring J, Hormuzdi S, Disteche CM, Bornstein P, Jaenisch R Trisomy eight in ES cells is a common potential problem in gene targeting and interferes with germ line transmission. Developmental dynamics : an official publication of the American Association of Anatomists. . 1997; 209(1): 85-91.
Liu X, Wu H, Byrne M, Krane S, Jaenisch R Type III collagen is crucial for collagen I fibrillogenesis and for normal cardiovascular development. Proceedings of the National Academy of Sciences of the United States of America. . 1997; 94(5): 1852-6.
Byrne M, Eeckhout Y, Henriet P, Lemaitre V, Jeffrey JJ, Witter J, Liu X, Wu H, Jaenisch R and Krane SM Different collagenase gene products have different roles in degradation of type I collagen. J. Biol. Chem. 1996; 271: 28509-28515.
Liu X, Wu H, Byrne M, Jeffrey J, Krane S, Jaenisch R A targeted mutation at the known collagenase cleavage site in mouse type I collagen impairs tissue remodeling. The Journal of cell biology. . 1995; 130(1): 227-37.
Wu H, Liu X, Jaenisch R and Lodish H Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell 1995; 83: 59-67.
Liu X, Enfors P, Wu H and Jaenisch R Sensory but not motor neuron deficits in mice lacking NT4 and BDNF. Nature 1995; 375: 238-241.
Andrikopoulos K, Liu X, Keene DR, Jaenisch R, Ramirez F Targeted mutation in the col5a2 gene reveals a regulatory role for type V collagen during matrix assembly. Nature genetics. . 1995; 9(1): 31-6.
Wu H, Liu X and Jaenisch R Double Replacement: A Strategy for Efficient Introduction of Subtle Mutations into Col1a1 gene by Homologous Recombination in ES Cells. Proc. Natl. Acad. Sci. USA 1994; 91: 2819-2823.
Liu X, Zwiebel LJ, Hinton D, Benzer S, Hall JC, Rosbash M The period gene encodes a predominantly nuclear protein in adult Drosophila. The Journal of neuroscience : the official journal of the Society for Neuroscience. . 1992; 12(7): 2735-44.
Zwieble L, Hardin P, Liu X, Hall J and Rosbash M A post-transcriptional mechanism contributes to circadian cycling of per-b-galactosidase fusion protein. Proc. Natl. Acad. Sci. USA 1991; 88: 3882-3886.
Liu X, Yu QA, Huang ZS, Zwiebel LJ, Hall JC, Rosbash M The strength and periodicity of D. melanogaster circadian rhythms are differentially affected by alterations in period gene expression. Neuron. . 1991; 6(5): 753-66.
Liu X, Lorenz L, Yu Q, Hall J and Rosbash M Spatial and temporal expression of the period gene in Drosophila melanogaster. Genes Dev. 1988; 2: 228-238.