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Scientific Report 2006
Molecular Biology
Lysophospholipid Signaling and Neural Aneuploidy
J. Chun, S. Appadurai, B. Almeida, B. Anliker, E. Birgbauer, A. Dubin, S. Gardell, D. Herr, G. Kennedy,
M. Kingsbury, C.W. Lee, M. Lu, M. McCreight, C. Paczkowski, S. Peterson, S. Rehen, R. Rivera, A.H. Yang, X.Q. Ye, Y. Yung, L. Zhu
In
the past year, we gained significant new insights into both lysophospholipid signaling
and neural aneuploidy. First, we discovered that receptor-mediated lysophosphatidic
acid (LPA) signaling, mediated by the cognate receptor known as LPA3,
is essential for normal implantation of embryos in the uterine wall, a finding that
may be relevant to the treatment of female infertility. Second, we acquired new
data that indicate the potential function of genomically nonidentical brain cells
in normal brain in humans. In further studies in mice, we found that aneuploid neurons
can be integrated into the normal circuitry of the brain, indicating that the neurons
are not simply dead or inert components but rather have the potential to modify
properties of neural circuitry by virtue of their altered genomes.
Lysophospholipids
Lysophospholipids such as LPA are
simple phospholipids that act as extracellular signals that use cognate G protein–coupled
receptors to bring about myriad effects. The 2 best studied lysophospholipids are
LPA and sphingosine 1-phosphate (S1P). We continue to generate new lines of mice
that lack the genes for single and multiple receptors and to characterize the mutant
phenotypes. A null mutation in LPA3 resulted in a reduced-fertility phenotype
that was attributed to alterations in embryo implantation (Fig. 1). We are elucidating
the downstream signaling effects of LPA3 in normal implantation.
Normal Neural Aneuploidy
It is now clear that many cells in
the brain have nonidentical genomes by virtue of being aneuploid, that is, the cells
have gained and/or lost chromosomes. The initial research on aneuploidy was done
in mice, raising the question of whether this phenomenon also existed in humans.
Use of double labeling with point probes, which recognize a relatively discrete
part of a chromosome, and “paints,” which recognize much of a given chromosome,
allowed the unambiguous identification of aneuploid neurons and glia in normal human
brain (Fig. 2). This finding led us to ask the additional question of whether such
cells were capable of normal function.
In mice, we found that indeed, aneuploid
neurons can have distant connections and physiologic activities, suggesting that
these genomically distinct cells can function in normal neural circuitry. Currently,
we are determining the extent, forms, and roles of aneuploid neural cells in normal
and diseased mammalian brains.
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| Fig. 1. Location
of implantation sites in uteri at embryonic days 4.5 (E4.5) and 5.5 (E5.5). Bands
indicate implantation sites. Mice lacking the gene for LPA3 have delayed
implantation and at later times have reduced and abnormally spaced implantation
(arrows). |
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| Fig. 2. Nuclei
isolated from the brains of different patients containing 1 (E), 2 (F), 3 (G), or
4 (H) copies of chromosome 21. The large, dark region indicates staining with DAPI
(4′,6-diamidino-2-phenylindole),
whole-chromosome paint appears in light gray, and the chromosome 21 point probes
are indicated by arrows. A complete overlap between the paint and the point probe
occurs, as seen at higher magnification in the insets. Arrowheads indicate the numbers
of chromosome 21 per cell. Scale bar, 5 μm. |
Publications
Barbeito, L., Chun, J., Binder,
L.I., Neto, V.M., Perry, G., Scazzochio, C., Violini, G. The
end of a Chilean institute. Science 308:792, 2005.
Chun, J. Lysophospholipids
in the nervous system. Prostaglandins Other Lipid Mediat. 77:46, 2005.
Gon, Y., Wood, M.R., Kiosses,
W.B., Jo, E., Sanna, M.G., Chun, J., Rosen, H. S1P3
receptor-induced reorganization of epithelial tight junctions compromises lung barrier
integrity and is potentiated by TNF. Proc. Natl. Acad. Sci. U. S. A. 102:9270, 2005.
Goparaju, S.K., Jolly, P.S.,
Watterson, K.R., Bektas, M., Alvarez, S., Sarkar, S., Mel, L., Ishii, I., Chun,
J., Milstien, S., Spiegel, S. The S1P2
receptor negatively regulates platelet-derived growth factor-induced motility and
proliferation. Mol. Cell. Biol. 25:4237, 2005.
Kingsbury, M.A., Friedman,
B., McConnell, M.J., Rehen, S.K., Yang, A.H., Kaushal, D., Chun, J. Aneuploid
neurons are functionally active and integrated into brain circuitry. Proc. Natl.
Acad. Sci. U. S. A. 102:6143, 2005.
Li, H., Ye, X., Mahanivong,
C., Bian, D., Chun, J., Huang, S. Signaling mechanisms
responsible for lysophosphatidic acid-induced urokinase plasminogen activator expression
in ovarian cancer cells. J. Biol. Chem. 280:10564, 2005.
Rehen, S.K., Yung, Y.C., McCreight,
M.P., Kaushal, D., Yang, A.H., Almeida, B.S.V., Kingsbury, M.A., Cabral, K.M.S.,
McConnell, M.J., Anliker, B., Fontanoz, M., Chun, J. Constitutional
aneuploidy in the normal human brain. J. Neurosci. 25:2176, 2005.
Simon, M.F., Daviaud, D., Pradere,
J.P., Grès, S., Guigné, C., Wabitsch, M., Chun, J., Valet, P., Saulnier-Blache,
J.S. Lysophosphatidic acid inhibits adipocyte differentiation
via lysophosphatidic acid 1 receptor-dependent down-regulation of peroxisome proliferator-activated
receptor γ2 J. Biol.
Chem. 280:1456, 2005.
Tölle, M., Levkau, B.,
Keul, P., Brinkmann, V., Giebing, G., Schönfelder, G., Schäfers, M., von
Wnuck Lipinski, K., Jankowski, J., Jankowski, V., Chun, J., Zidek, W., Van der Giet,
M. Immunomodulator FTY720 induces eNOS-dependent
arterial vasodilation via the lysophospholipid receptor S1P3. Circ. Res.
96:913, 2005.
Ye, X., Hama, K., Contos, J.J.,
Anliker, B., Inoue, A., Skinner, M.K., Suzuki, H., Amano, T., Kennedy, G., Arai,
H., Aoki, J., Chun, J. LPA3 lysophosphatidic
acid signalling in embryo implantation and spacing. Nature 435:104, 2005.
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