Signaling by the secreted Wnt family of lipoproteins regulate many fundamental aspects of embryogenesis and tissue homeostasis. Deregulated Wnt signaling has been implicated in human diseases including birth defects, cancer, osteoporosis and degenerative disorders. The study of the mechanisms of Wnt signaling thus has critical importance for understanding basic biology and human health, and for potential disease treatment. In addition to Wnt proteins, distinct families of secreted and membrane-bound Wnt agonists and antagonists have been found that enhance or inhibit Wnt signaling during embryonic development and in physiological or pathological conditions. These Wnt modulators regulate Wnt signaling output in stage- and/or tissue-specific manner and often underlie diverse functions that Wnt pathways control, and they represent potential therapeutic targets for Wnt-related pathogenesis. The Xenopus embryo has been a powerful model system for the discovery and characterization of many families of Wnt modulators in vertebrate embryogenesis. Building on our previous success in this area, this renewal application will focus on the mechanisms and functions of two families of Wnt antagonists.
Aim 1 is to study the Tiki protein, a novel Wnt-inactivating enzyme that we identified and is required for Xenopus anterior patterning. Tiki is the first example of Wnt signaling inhibition through enzymatic inactivation of the ligand, and represents the founding member of a new metalloprotease clan that is conserved from pathogenic bacteria to human. We will characterize Tiki enzymatic function, Wnt cleavage specificity, and its mechanism in regulating different Wnt signaling pathways.
Aim 2 and Aim 3 are to study the molecular basis and biological functions of another conserved Wnt antagonist during Xenopus embryogenesis. The mechanism by which this Wnt antagonist operates is not fully understood, and will be investigated in Aim 2 using conventional and advanced molecular and biochemical techniques. Based on our findings that the Wnt antagonist is expressed maternally and during cleavage and gastrulation stages of Xenopus embryos, its potential roles in regulating Wnt-mediated dorsoventral and anteroposterior patterning in different developmental stages will be investigated in Aim 3. These molecular and embryological experiments together will likely provide novel insights into Wnt signaling regulation and vertebrate embryogenesis.

Public Health Relevance

Cell-to-cell communication is vital for embryonic development and tissue homeostasis. One of the major cell communication routes is through the extracellular WNT protein, which instructs cells to proliferate or differentiate. Abnormal activities of WNT signaling cause human birth defects, cancer, osteoporosis, and other diseases. WNT functions are regulated by many extracellular inhibitors, the so-called 'WNT antagonists', which are directly involved in human pathogenesis. This application aims to investigate the mechanisms and functions of two different WNT antagonists, using mammalian cells and frog embryos as experimental systems. These studies will likely provide new insights into cell-to-cell communication and vertebrate embryonic development, and will have implications to understanding human birth defects, cancer pathogenic mechanisms, and potential disease treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057603-16
Application #
9281545
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Gibbs, Kenneth D
Project Start
1999-04-01
Project End
2019-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
16
Fiscal Year
2017
Total Cost
$436,992
Indirect Cost
$190,104
Name
Boston Children's Hospital
Department
Type
Independent Hospitals
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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