Gastrulation movements establish the germ layers and animal body plan during embryogenesis. Convergence and extension (C&E) are key gastrulation movements that narrow the germ layers along the mediolateral embryonic axis while extending their anteroposterior dimension. A non-canonical Wnt/planar cell polarity (Wnt/PCP) pathway, including its components Knypek (Glypican 4;Kny/Gpc4) and Trilobite (Van gogh like 2;Tri/Vangl2), is a major regulator of polarized cell behaviors driving C&E in all vertebrates. We showed that in the mediolaterally elongated cells engaged in C&E some PCP components become enriched near the anterior, others at the posterior cell membrane, whereas protrusive activity is confined largely to the medial and lateral cell edges. Here we propose to address the key outstanding questions of the intracellular mechanisms via which the Wnt/PCP pathway regulates cell polarity, and the coordination of the cellular with embryonic polarity.
Our Aim1 is to test the hypothesis that the microtubule network and Wnt/PCP pathway interact to establish and maintain distinct properties of the anterior, posterior, medial and lateral cell edges. We will ask if gastrula cells require Clasp1 function and have microtubules that are asymmetrically nucleated at the Golgi in a Clasp1-dependent fashion.
Aim 2 is to delineate the mechanism via which ugly duckling (udu) gene, which interacts with kny/gpc4 and encodes a putative chromatin regulator, influences C&E. We will first characterize defective gastrulation movements and patterning in embryos depleted of zygotic and maternal udu function. We will test whether Udu, a SANT domain containing protein, regulates covalent histone modifications Finally, will identify genes that are regulated by udu during gastrulation via gene expression profiling.
In Aim 3 we will test whether Fat and Dachsous protocadherins regulate the Wnt/PCP pathway during C&E movements. We will generate mutations in zebrafish fat1-4 and dachsous1 and 2 genes, analyze their single and compound phenotypes and interactions with the PCP pathway components. Our work will delineate the mechanisms whereby Wnt/PCP signaling regulates intracellular asymmetries within mesenchymal cells in vivo. We will identify pathways that interact with the Wnt/PCP pathway to coordinate the embryonic and cell polarity.

Public Health Relevance

Convergence and extension is a key process shaping embryonic tissues. The Wnt/PCP pathway emerged as a universal regulator of this process. In humans, mutations in Wnt/PCP pathway genes have been identified as a risk factor for neural tube defects. In addition, Fat genes have been implicated in control of organ size and recently emerged as candidates for tumor suppressor genes. This work will delineate the mechanisms via which Wnt/PCP pathway regulates cell movements during embryogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM055101-16
Application #
8600686
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Hoodbhoy, Tanya
Project Start
1997-01-01
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
16
Fiscal Year
2014
Total Cost
$342,006
Indirect Cost
$117,002
Name
Washington University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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