| dc.description.abstract |
<p>Basement membrane (BM) is a dense, conserved sheet-like extracellular matrix that
provides structural support, compartmentalizes tissues, and regulates cell behaviors.
Despite the barrier-like properties of BM, cell invasion through BM takes place normally
in many developmental and physiological processes. Deregulation of cell invasion causes
a variety of human diseases, most notably, cancer metastasis. A better understanding
of cell invasion would help in the design more effective therapeutic strategies for
those diseases.</p><p> Cell invasion through BM is a dynamic process comprising
multiple intertwined steps, including acquirement of polarized cellular morphology,
BM breaching, and BM remodeling. Despite much effort on investigating cellular invasive
programs used for BM penetration, little is know about how cells detect invasive cues
that polarize the invasive responses. Although the establishment of invasive polarity
is critical as it initiates subsequent invasive behavior, the invasion process would
not be completed without effective BM remodeling. Given that BM remodeling is often
an integral part of tissue morphogenesis, the underlying interactions among cells
and surrounding tissues make it challenging to understand the individual contributions
of cells to changes in BM structure. </p><p> To gain insight into these two questions
requires simple, experimental in vivo models. Anchor cell (AC) invasion into the vulval
epithelium in C. elegans provides a visually accessible and experimentally tractable
invasion model that is particularly suitable for cell biological and genetic analysis
of the complicated interplay among local BM, an invading cell and the surrounding
tissues. Using this model, I have investigated (1) how the AC detects dynamically
expressed and localized netrin, a polarizing invasive cue for the AC; (2) what the
functional contribution of the AC (as an invading cell) is to BM remodeling during
uterine-vulval attachment, a post-embryonic organogenesis process. </p><p> First,
I found that localized netrin polarizes the cellular invasive response towards the
BM by stabilizing and spatially orienting a novel receptor-induced polarity oscillation.
This oscillation is characterized by periodic F-actin assembly and disassembly at
random sites of the plasma membrane of the AC. I have found F-actin assembly is accompanied
by the formation of cellular protrusions. Strikingly, when these protrusions contact
localized netrin, they are stabilized. Thus, I propose a mechanistic model where the
ligand-independent activity of the receptor generates exploratory behavior. This mechanism
orients the invasive polarity of the AC towards its BM target where netrin is normally
localized. Second, taking advantage of an unbiased mutagenesis screen, I characterized
a mutant with defects in BM sliding, a newly uncovered BM remodeling mechanism. I
found that the invading AC utilizes a conserved transcription factor to control the
initiation of BM sliding, which involves the regulation of integrin-mediated cell-matrix
adhesion. Thus, my study revealed a novel functional role for the AC in BM remodeling
during tissue restructuring.</p>
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