gap junction
mediated cell-cell signaling in cardiovascular development
One of the main research interests
in the laboratory is examining the of the role of gap junction
communication in the regulation of mammalian embryogenesis. Gap
junctions are cell junctions containing membrane channels that
allow the free cell-to-cell movement of ions, second messengers,
and metabolites. They provide an intracellular pathway for the
propagation and/or amplification of signal transduction cascades
triggered by cytokines, growth factors and other cell signaling
molecules involved in growth regulation and development. Our recent
studies using trangsenic and knockout mouse models have indicated
an important role for the connexin 43 (Cx43) gap junctions in
modulating events in mammalian cardiac development. This appears
to involve a role for gap junction communication in the regulation
of neural crest migration and development. We are now using various
in vitro and in vivo experimental approaches to elucidate
the underlying cellular and molecular mechanisms by which gap
junction communication may serve to regulate neural crest migration
and development. This includes the analysis of the signal transduction
pathways which may be modulated by gap junction mediated cell-cell
communication. For these studies additional transgenic mouse models
are being generated, including the use of targeted knockin and
conditional knockout approaches. We are also further pursuing
studies to elucidate how crest perturbation may affect cardiac
structure and function using Doppler echocardiography and MRI
analysis. Such studies are aimed at obtaining further insights
into the possible clinical relevance of these mouse models to
human cardiovascular disease.
A second area of research interest
involves the examination of the genes that regulate mammalian
left/right patterning. Our research interest in this area was
in part sparked by the finding that humans with defects in left/right
patterning clinically referred to as visceroatrioheterotaxy (VAH)
harbor point mutations in the cytoplasmic tail of the Cx43 gap
junction protein (Britz-Cunningham et al., 1996). This finding
was extended by recent studies in the Xenopus model system
where laterality defects were observed to arise from the perturbation
of gap junction communication during early stages of Xenopus embryonic
development. Our research interest in the left/right patterning
field are two fold. First, we are pursuing studies to examine
the role of Cx43 gap junctions in left/right patterning. For these
studies we are making a knockin mouse model with the human Cx43
mutation found in VAH patients. The analysis of left/right patterning
in these mice may provide further clues as to the role of Cx43
gap junctions in the specification of left/right patterning. A
second line of investigation is in examining a novel mutation
we have recovered which causes laterality defects. This mutation
is referred to as no turning, as the embryos fail to undergo embryonic
turning. This mutant is particularly interesting as it exhibits
left/right patterning defect in conjunction with defects along
the anterior/posterior axis. Efforts are currently underway to
map this mutation in the mouse genome by breeding the mutation
into Castanus mice and carrying out a genome scan with RFLP markers.
These studies are to be followed by efforts to find candidate
genes and also the positional cloning of this gene.
selected
publications
Melloy, P.G., Ewart, J.L., Cohen,
M.F., Desmond, M.E., Kuehn, M.R., and C. W. Lo. 1998. No
turning, a novel mouse mutation causing defects in left-right
and axial patterning. Dev. Biol. 193:77-89.
Huang, G.Y., Wessels, A., Smith, B.R.,
Linask, K.K., Ewart, J.L., Lo, C. W. 1998. Alteration in
connexin 43 gap junction gene dosage impairs conotruncal heart
development. Dev. Biol. 198:32-44.
Lo, C.W., and Wessels, A. 1998.
Cx43 gap junctions and cardiac development. Trends in Cardiovascular
Medicine 8: 266-271.
Hough, R.B. Lengeling, A., Bedian,
V., Lo, C.W., and Bucan, M. 1998. The Rump white
(Rw) inversion in the mouse disrupts dipeptidyl aminopeptidase
like protein 6 (Dpp6) and causes dysregulation of Kit expression.
Proc. Natl. Acad. Sci. 95:13800-13805.
Sullivan, R., Meyer,R., Huang, G.Y.,
Cohen, M.F. Wessels, A., Linask, K.K. and C.W. Lo. 1998.
Heart malformations in transgenic mice exhibiting dominant negative
inhibition of gap junctional communication. Dev. Biol. 204:2242-234.
Huang, G.Y., Cooper, E.S., Waldo, K.,
Kirby, M.L., Gilula, N.B., and Lo, C.W. 1998. Gap junction
mediated cell-cell communication modulates mouse neural crest
migration. J. Cell Bio. 143:1725-1734.
Lo, C.W., and Gilula, N.B. 1999.
Gap Junctional communication in mbryogenesis and development.
Advances in Molecular and Cell Biology, Vol. 29: Gap Junctions.
E. Bittar, ed.; E.L. Hertzberg, guest editor. JAI Press, Stamford,
CT. In press.
Waldo, K.L., and Lo, C.W., and
Kirby, M.L. 1999. Cx43 expression reflects neural crest pattern
during cardiovascular development. Dev. Biol. 208:307-323.
Lo, C.W. 1999. Genes, gene knockouts,
and mutations in the analysis of gap junctions. Dev. Genet.24:1-4.
Lo, C.W., Waldo, K.L., and Kirby,
M.L. 1999. Gap junction communication and the modulation of cardiac
neural crest cells. Trends in Cardiovas. Med.9:63-69.
Morley, G.E., Vaidya, D., Samie, F.H.,
Lo, C.W., Delmar, M., and Jalife, J. 1999. Characterization
of conduction in the mouse ventricle using optical mapping. J.
Cardiovascular Electrophysiology199910:1361-1375.
Gourdie, R.G., and Lo, C.W.
1999. Cx43 (µ1)
gap junction in cardiac development and disease. Current Topics
in Membranes. 49:581-602.
Lo, C.W., and Gilula, N.B. 2000.
Gap Junctional communication in embryogenesis and development.
Advances in Molecular and Cell Biology, Gap Junctions.
Vol. 29: pp.193-219. E. Bittar, ed.; E.L. Hertzberg, guest editor.
JAI Press, Stamford, CT.
Epstein, J.A., Li, J., Lang, D., Chen,
F., Brown, C., Jin, F., Thomas, M., Liu, E.-C.J., Wessels, A.,
and Lo, C.W. 2000. Migration of cardiac neural crest cells
in Splotch embryos. Development127:1869-1878.
Waller, III, B.R., A.L., Phelps, Markwald,
R.R., Lo, C.W., Thompson, R.P., and Wessels, A. 2000. Murine
trisomy 16 as a model for conotruncal anomalies in DiGeorge Syndrome.
Anat. Rec.In press.
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