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Published on: October 1, 2007
Dose-dependent functions of Fgf8 in regulating telencephalic patterning centers
Elaine E Storm1, Sonia Garel, Ugo Borello
1Department of Anatomy, University of California, San Francisco, CA 94143-2711, USA.
Abstract:
Mouse embryos bearing hypomorphic and conditional null Fgf8 mutations have small and abnormally patterned telencephalons. We provide evidence that the hypoplasia results from decreased Foxg1 expression, reduced cell proliferation and increased cell death. In addition, alterations in the expression of Bmp4, Wnt8b, Nkx2.1 and Shh are associated with abnormal development of dorsal and ventral structures. Furthermore, nonlinear effects of Fgf8 gene dose on the expression of a subset of genes, including Bmp4 and Msx1, correlate with a holoprosencephaly phenotype and with the nonlinear expression of transcription factors that regulate neocortical patterning. These data suggest that Fgf8 functions to coordinate multiple patterning centers, and that modifications in the relative strength of FGF signaling can have profound effects on the relative size and nature of telencephalic subdivisions.
Insights
Fibroblast growth factor 8 (FGF8) signaling is crucial for telencephalon development in mouse embryos. Reduced FGF8 signaling leads to smaller brains, altered gene expression, and abnormal patterning, impacting brain structure formation.
Area of Science:
- Developmental biology
- Neuroscience
- Genetics
Background:
- Fibroblast growth factor 8 (FGF8) is a key signaling molecule in embryonic development.
- Proper telencephalon development is essential for brain function.
- FGF8 mutations can lead to severe developmental defects.
Purpose of the Study:
- To investigate the role of FGF8 in telencephalon patterning and development.
- To elucidate the molecular mechanisms underlying FGF8-mediated brain development.
- To understand the consequences of altered FGF8 signaling on gene expression and cellular processes.
Main Methods:
- Utilized mouse models with hypomorphic and conditional null Fgf8 mutations.
- Analyzed telencephalon size, patterning, cell proliferation, and cell death.
- Examined the expression patterns of key developmental genes (Foxg1, Bmp4, Wnt8b, Nkx2.1, Shh, Msx1).
Main Results:
- Fgf8 mutations resulted in smaller, abnormally patterned telencephalons.
- Hypoplasia was linked to decreased Foxg1 expression, reduced proliferation, and increased cell death.
- Altered expression of Bmp4, Wnt8b, Nkx2.1, and Shh was observed.
- Nonlinear Fgf8 gene dose effects correlated with holoprosencephaly and altered transcription factor expression.
Conclusions:
- FGF8 signaling coordinates multiple patterning centers during telencephalon development.
- Modulating FGF8 signaling strength profoundly impacts telencephalic subdivision size and characteristics.
- FGF8 is critical for regulating gene expression networks essential for neocortical patterning.
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