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

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.