Biomedical Sciences Graduate Program(s)
Biomedical Sciences Graduate Programs
Cell polarity is tightly coupled to specialized cell functions and is
fundamental to many cellular processes in development and disease. Two forms
of epithelial polarity have been observed: one along the apical-basal axis,
and one orthogonal to the apical-basal axis known as planar cell polarity
(PCP). The Lu lab is interested in dissecting the signaling events that
generate planar asymmetry and the resulting cellular behaviors during
mammalian development, with a specific focus on two types of polarized cells
in the nervous system, namely neuroepithelial cells and neurons.
It has been shown that an evolutionarily conserved noncanonical,
b-catenin-independent Wnt pathway regulates PCP and is involved in diverse
processes such as neural tube closure and cochlear hair cell morphogenesis.
Recently, in a gene trap screen in the mouse, we identified PTK7, an
atypical receptor tyrosine kinase, as a novel regulator of PCP in
vertebrates. Interestingly, homologs of several vertebrate PCP genes,
including PTK7, have not been implicated in PCP signaling in Drosophila,
suggesting that vertebrates have evolved novel strategies to regulate PCP.
Using PTK7 as an entry point, we are taking a combination of biochemical,
genetic and cell biological approaches to further elucidate signaling
mechanisms by which the PCP pathway exert its effect on cellular machinery,
such as the cytoskeleton and protein trafficking network.
The cochlear sensory epithelium of the mouse offers an attractive system to
study PCP at a single cell resolution both in vivo and in organotypic
cultures. PCP is manifested by the asymmetric orientation of the hair cell
stereocilia, an actin-rich structure responsible of mechanotransduction.
Using a variety of genetic and molecular manipulations and imaging
techniques, experiments are underway to better understand the sequence of
events that lead to coordinated polarized outgrowth of stereocilia across
the sensory epithelium.
We are extending our analysis of the PCP pathway into the development of the
central nervous system. Our preliminary analysis of mutant phenotype
suggests that PCP pathway is involved in patterning certain regions of the
CNS. Currently we are investigating the molecular pathway that underlies the
patterning defect. Furthermore, aided by expression studies, we hypothesize
that PCP signaling also functions in later aspects of CNS development, such
as cell and axon migration and target selection. We plan to use transgenic
mice and in vitro neuronal cultures to test this hypothesis.
Ultimately, we hope that our studies will shed light on how the versatile
PCP pathway controls cell polarity in different contexts during normal
development and how mutations disrupt polarity in related human disease and
Friedel, R.H., Plump, A., Lu, X., Spilker, K., Jolicoeur, C., Wong, K.,Venkatesh, T., Yaron, A., Hynes, M., Chen, B., Okada, A., McConnell, S.K., Rayburn, H. and Tessier-Lavigne, M. (2005). Gene targeting using a promoterless gene trap vector (³targeted trapping²) is an efficient method to mutate a large fraction of genes. PNAS, in press.
Lu, X., Le Noble, F., Yuan, L., Jiang, Q., De Lafarge, B. P., Sugiyama, D., Bréant, C., Claes, F., De Smet, F., Thomas, J-L., Autiero, M., Carmeliet. P., Tessier-Lavigne, M. and Eichmann, A. (2004) The Netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system. Nature 432, 179-186. (*These authors contributed equally to this work.)
Lu, X., Borchers, A., Jolicoeur, C., Rayburn, H., Baker, J. C. and
Tessier-Lavigne, M. (2004) PTK7/CCK-4 is a novel regulator of planar cell
polarity in vertebrates. Nature 430, 93-98.
Leighton, P. A.*, Mitchell, K. J.*, Goodrich, L. V.*, Lu, X., Pinson, K., Scherz, P., Skarnes, W. C., and Tessier-Lavigne, M. (2001). Defining brain wiring patterns and mechanisms through gene trapping in mice. Nature 410, 174-179. (*These authors contributed equally to this work.)
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