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Serum response factor is essential for mesoderm formation during mouse embryogenesis
S Arsenian1, B Weinhold, M Oelgeschläger
1Institut für Molekularbiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
Abstract:
The transcription factor serum response factor (SRF), a phylogenetically conserved nuclear protein, mediates the rapid transcriptional response to extracellular stimuli, e.g. growth and differentiation signals. DNA- protein complexes containing SRF or its homologues function as nuclear targets of the Ras/MAPK signalling network, thereby directing gene activities associated with processes as diverse as pheromone signalling, cell-cycle progression (transitions G0-G1 and G2-M), neuronal synaptic transmission and muscle cell differentiation. So far, the activity of mammalian SRF has been studied exclusively in cultured cells. To study SRF function in a multicellular organism we generated an Srf null allele in mice. SRF-deficient embryos (Srf -/-) have a severe gastrulation defect and do not develop to term. They consist of misfolded ectodermal and endodermal cell layers, do not form a primitive streak or any detectable mesodermal cells and fail to express the developmental marker genes Bra (T), Bmp-2/4 and Shh. Activation of the SRF-regulated immediate early genes Egr-1 and c-fos, as well as the alpha-Actin gene, is severely impaired. Our study identifies SRF as a new and essential regulator of mammalian mesoderm formation. We therefore suggest that in mammals Ras/MAPK signalling contributes to mesoderm induction, as is the case in amphibia.
Insights
Serum response factor (SRF) is essential for mammalian mesoderm formation. SRF-deficient embryos exhibit severe gastrulation defects, highlighting its critical role in early development.
Area of Science:
- Developmental Biology
- Molecular Biology
- Genetics
Background:
- Serum response factor (SRF) is a conserved transcription factor regulating cellular responses to stimuli.
- SRF is a target of the Ras/MAPK signaling network, influencing diverse cellular processes.
- Previous SRF studies were limited to cultured cells, lacking in vivo multicellular organism data.
Purpose of the Study:
- To investigate the function of SRF in a multicellular organism.
- To determine the role of SRF in mammalian embryonic development and mesoderm formation.
Main Methods:
- Generation of a null allele for SRF in mice (Srf -/-).
- Analysis of SRF-deficient embryos for developmental defects and gene expression.
- Assessment of SRF-regulated immediate early genes and muscle-specific genes.
Main Results:
- SRF-deficient embryos display severe gastrulation defects and do not survive to term.
- Absence of primitive streak and mesodermal cells in Srf -/- embryos.
- Impaired expression of developmental markers (Bra, Bmp-2/4, Shh) and SRF-regulated genes (Egr-1, c-fos, alpha-Actin).
Conclusions:
- SRF is identified as a novel and essential regulator of mammalian mesoderm formation.
- Ras/MAPK signaling likely contributes to mesoderm induction in mammals, similar to amphibians.