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| The EMBO Journal
(2000) 19, 5835–5844, doi:10.1093/emboj/19.21.5835 |
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| Srf-/- ES cells display non-cell-autonomous impairment in mesodermal differentiation |
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| Birgit Weinhold1, 2, 7, Gerhard Schratt3, 7, Sergei Arsenian3, Jürgen Berger4, Kenji Kamino5, Heinz Schwarz4, Ulrich Rüther1, 6 and Alfred Nordheim3 |
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1 Institut für Molekularbiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany 2 Present address: Institut für Medizinische Mikrobiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany 3 Interfakultäres Institut für Zellbiologie, Abteilung Molekularbiologie, Universität Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany 4 Max-Planck-Institut für Entwicklungsbiologie, Spemannstrasse 35, 72074 Tübingen, Germany 5 Institut für Pathologie, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany 6 Entwicklungs- und Molekularbiologie der Tiere, Heinrich Heine Universität, Universitätsstrasse 1, 40225 Düsseldorf, Germany 7 B.Weinhold and G.Schratt contributed equally to this work To whom correspondence should be addressed Alfred Nordheim, alfred.nordheim@uni-tuebingen.de Received 11 July 2000; Revised 28 August 2000; Accepted 8 September 2000. |
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| Abstract |
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| 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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| Keywords: embryoid bodies, embryonic stem cells, mesoderm induction, murine embryogenesis, serum response factor |
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