Xiaowei Lu

Education

  • BS, Beijing University
  • PhD, Massachusetts Institute of Technology
  • Postdoc, University of California, San Francisco

Primary Appointment

  • Associate Professor, Cell Biology

Contact

Research Interest(s)

Developmental regulation of planar cell polarity in the mammalian nervous system

Research Description

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
birth defects.

Selected Publications

  • Sipe C, Lu X. Kif3a regulates planar polarization of auditory hair cells through both ciliary and non-ciliary mechanisms. Development (Cambridge, England). 2011;138(16): 3441-9. PMID: 21752934 | PMCID: PMC3143564
  • Paudyal A, Damrau C, Patterson V, Ermakov A, Formstone C, Lalanne Z, Wells S, Lu X, Norris D, Dean C, Henderson D, Murdoch J. The novel mouse mutant, chuzhoi, has disruption of Ptk7 protein and exhibits defects in neural tube, heart and lung development and abnormal planar cell polarity in the ear. BMC developmental biology. 2010;10 87. PMID: 20704721 | PMCID: PMC2930600
  • Grimsley-Myers C, Sipe C, Géléoc G, Lu X. The small GTPase Rac1 regulates auditory hair cell morphogenesis. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2009;29(50): 15859-69. PMID: 20016102 | PMCID: PMC2847287
  • Yen W, Williams M, Periasamy A, Conaway M, Burdsal C, Keller R, Lu X, Sutherland A. PTK7 is essential for polarized cell motility and convergent extension during mouse gastrulation. Development (Cambridge, England). 2009;136(12): 2039-48. PMID: 19439496 | PMCID: PMC2685725
  • Andersen E, Lu X, Horvitz H. C. elegans ISWI and NURF301 antagonize an Rb-like pathway in the determination of multiple cell fates. Development (Cambridge, England). 2006;133(14): 2695-704. PMID: 16774993
  • Harrison M, Ceol C, Lu X, Horvitz H. Some C. elegans class B synthetic multivulva proteins encode a conserved LIN-35 Rb-containing complex distinct from a NuRD-like complex. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(45): 16782-7. PMID: 17075059 | PMCID: PMC1636532
  • Williams M, Lu X, McKenna W, Washington R, Boyette A, Strickland P, Dillon A, Kaprielian Z, Tessier-Lavigne M, Hinck L. UNC5A promotes neuronal apoptosis during spinal cord development independent of netrin-1. Nature neuroscience. 2006;9(8): 996-8. PMID: 16829956
  • Friedel R, Plump A, Lu X, Spilker K, Jolicoeur C, Wong K, Venkatesh T, Yaron A, Hynes M, Chen B, Okada A, McConnell S, Rayburn H, Tessier-Lavigne M. Gene targeting using a promoterless gene trap vector ("targeted trapping") is an efficient method to mutate a large fraction of genes. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(37): 13188-93. PMID: 16129827 | PMCID: PMC1193537
  • Lu X, Le Noble F, Yuan L, Jiang Q, De Lafarge B, Sugiyama D, Bréant C, Claes F, De Smet F, Thomas J, Autiero M, Carmeliet P, Tessier-Lavigne M, Eichmann A. The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system. Nature. 2004;432(7014): 179-86. PMID: 15510105