All tissues of the vertebrate body arise from three primary germ layers;the ectoderm, mesoderm and endoderm. The ectoderm gives rise to the central nervous system and epidermis. Its development is poorly understood, compared with the other two germ layers. We have recently identified a forkhead-type transcription factor, Foxi1e, that is expressed from the start of zygotic transcription in the region that gives rise to the ectoderm, and is essential for formation of both nervous system and epidermis. Preliminary and published data show that Foxi1e is an essential zygotic activator of ectoderm. However, Foxi1e is not expressed in all cells that will form the ectoderm. Instead it is expressed in a mosaic pattern, with expressing cells intermingled with non-expressing cells. We have shown that local signaling through the Notch pathway, and global signals released by the vegetal cells of the embryo (which form the endoderm), combine to control the expression pattern of Foxi1e. This project aims to identify the mechanism by which these signaling pathways generate the pattern of Foxi1e, and the mechanism by which its mosaic expression pattern gives rise to the ectodermal tissues of the embryo. A great deal of preliminary data has been assembled, including the identification of maternal activators and repressors of Foxi1e expression, as well as a novel Wnt signaling pathway in the ectoderm-forming region of the embryo, Affymetrix screens for genes whose expression is changed by Foxi1e depletion in the embryo, and by Notch signaling. At the end of the project we aim to establish, for the first time, the outline of a molecular pathway leading from the egg to the ectodermal tissues of the embryo.

Public Health Relevance

Narrative: All tissues of the body arise from three layers of tissue that form in the early embryo. These are known as the three primary germ layers. The ectoderm germ layer gives rise to the brain and spinal cord, and the epidermis of the skin. Despite the importance of the ectoderm, surprisingly little is known about how it forms in the embryo. Using the Xenopus embryo, we aim to establish the molecular mechanism of ectoderm formation. We have identified a transcription factor, expressed in the region of the embryo which will form the ectoderm, which is absolutely required for normal development of the brain spinal cord, and epidermis. Surprisingly, it is expressed in a mosaic pattern in the pre-ectodermal cells;expressing cells are intermingled with non-expressing cells, and yet all cells will go on to form the ectodermal tissues. This project aims to identify the molecular mechanism that generates the mosaic pattern, and the mechanism by which a mosaic pattern of expression of a transcription factor can give rise to the ectoderm.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD045737-09
Application #
8446373
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Mukhopadhyay, Mahua
Project Start
2004-02-12
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
9
Fiscal Year
2013
Total Cost
$289,233
Indirect Cost
$100,192
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Mir, Adnan; Kofron, Matthew; Heasman, Janet et al. (2008) Long- and short-range signals control the dynamic expression of an animal hemisphere-specific gene in Xenopus. Dev Biol 315:161-72
Mir, Adnan; Kofron, Matt; Zorn, Aaron M et al. (2007) FoxI1e activates ectoderm formation and controls cell position in the Xenopus blastula. Development 134:779-88
Houston, Douglas W; Wylie, Christopher (2005) Maternal Xenopus Zic2 negatively regulates Nodal-related gene expression during anteroposterior patterning. Development 132:4845-55