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Intercellular Signaling Pathways in the Initiation of Mammalian Forebrain Development

by Yang, Yu-Ping

Abstract (Summary)
The Spemann organizer in amphibians gives rise to the anterior mesendoderm

(AME) and is capable of inducing neural tissues. This inductive activity is thought to

occur largely via the antagonism of Bone Morphogenetic Protein (BMP) signaling in the

organizer. In the mouse, BMP antagonists Chordin and Noggin function redundantly in

the AME and are required during forebrain maintenance. However, the timing of

forebrain initiation and the function of BMP antagonism in forebrain initiation remained

unclear prior to this study. In addition, the Transforming Growth Factor ? (TGF?) ligand

Nodal patterns the forebrain via its function in the anterior primitive streak (APS), the

precursor tissue of the AME. Whether BMP and Nodal signaling pathways interact has

not been previously investigated.

The goal of this dissertation was to investigate the cellular and molecular

mechanisms involved in early mammalian forebrain establishment by embryonic and

genetic manipulations. This study determined that forebrain initiation occurs during

early gastrulation and requires signals from the AVE and AME. The AVE was identified

as a source of active BMP antagonism in vivo, and the BMP antagonism supplied by

exogenous tissues was capable to promote forebrain initiation and maintenance in the

murine ectoderm. It is likely that BMP antagonism enhances forebrain gene expression

via inhibiting posteriorization. This study further identified a possible crosstalk between

BMP and Nodal signaling. Loss of Chordin or Noggin in combination with heterozygosity

for Nodal or Smad3 results in holoprosencephaly. Molecular analyses suggest that the

BMP-Nodal interaction occurs in the APS and/or the AME. Failure of this interaction

results in an imbalance of BMP and Nodal signal levels that devastate APS and AME

patterning during early forebrain establishment, ultimately leading to holoprosencephaly

in mid-gestation. This interaction is likely to occur extracellularly, possibly by formation

of a BMP-Nodal heteromeric complex. Furthermore, the spatiotemporal expression of

phospho-Smad1/5/8, an effector of BMP signaling pathway, was characterized during

early mouse embryogenesis. Distribution of phospho-Smad1/5/8 serves as a faithful

readout of BMP signaling activity and helps to better understand how BMPs are

involved in patterning early embryos. The implication of phospho-Smad1/5/8

expression in both wildtype and mutant embryos is also discussed.

Bibliographical Information:

Advisor:Klingensmith, John; Capel, Blanche; Kirby, Margaret L.; Linney, Elwood A.; McClay, David R.

School:Duke University

School Location:USA - North Carolina

Source Type:Master's Thesis

Keywords:amphibians anterior mesendoderm ame bone morphogenetic protein bmp embryos mammals forebrain

ISBN:

Date of Publication:05/03/2007

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