Srf–/– ES cells display non-cell-autonomous impairment in mesodermal differentiation

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Oxford University Press

RESUMO

The serum response factor (SRF) transcription factor is essential for murine embryogenesis. Srf–/– embryos stop developing at the onset of gastrulation, lacking detectable mesoderm. This developmental defect may reflect cell-autonomous impairment of Srf–/– embryonic cells in mesoderm formation. Alternatively, it may be caused by a non-cell-autonomous defect superimposed upon inappropriate provision of mesoderm-inducing signals to primitive ectodermal cells. We demonstrate that the ability of Srf–/– embryonic stem (ES) cells to differentiate in vitro into mesodermal cells is indeed impaired. However, this impairment can be modulated by external, cell-independent factors. Retinoic acid, but not dimethylsulfoxide, permitted activation of the mesodermal marker gene T(Bra), which was also activated when SRF was expressed in Srf–/– ES cells. Embryoid bodies from Srf–/– ES cell aggregates also activated mesodermal marker genes, but displayed unusual morphologies and impairment in cavitation. Finally, in nude mice, Srf–/– ES cells readily differentiated into mesodermal cells of Srf–/– genotype, including cartilage, bone or muscle cells. We demonstrate that SRF contributes to mesodermal gene expression of ES cells and that Srf–/– ES cells display a non-cell-autonomous defect in differentiation towards mesoderm.

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