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.
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.
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.
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.
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.
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.
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.
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, 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.
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.
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.
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.
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.
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.
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.
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.
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.
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Our research aims at understanding the molecular basis of nervous system development, plasticity, and neurodegenerative diseases. We use gene targeting in mice and focus on neurotrophins, Delta-catenin, and PTEN.
NEUROTROPHINS
Neurotrophins (NTs) study has had 56 years of history and is the largest field in neuroscience. In the center of this study is neurotrophins' 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 neurotrophins' 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.
DELTA-CATENIN
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 Alzheimer's 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 Alzheimer's disease (AD). We knocked out d-cat and found that d-cat is an important molecule in synaptic plasticity (Israely, el.al., 2004). 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.
PTEN
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 it's 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 pert urbing its differentiation program (Groszer et al., 2001). 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., 2004, submitted).
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 whet her 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 sig nal 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., 2004, manuscript in preparation).
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