The Docking Protein FRS2α Is an Essential Component of Multiple Fibroblast Growth Factor Responses during Early Mouse Development

Abstract

The docking protein FRS2α is a major mediator of fibroblast growth factor (FGF) signaling. However, the physiological role of FRS2α in vivo remains unknown. In this report, we show that Frs2α-null mouse embryos have a defect in anterior-posterior (A-P) axis formation and are developmentally retarded, resulting in embryonic lethality by embryonic day 8. We demonstrate that FRS2α is essential for the maintenance of self-renewing trophoblast stem (TS) cells in response to FGF4 in the extraembryonic ectoderm (ExE) that gives rise to tissues of the placenta. By analyzing chimeric embryos, we found that FRS2α also plays a role in cell movement through the primitive streak during gastrulation. In addition, experiments are presented demonstrating that Bmp4 expression in TS cells is controlled by mitogen-activated protein kinase-dependent FGF4 stimulation. Moreover, both the expression of Bmp4 in ExE and activation of Smad1/5 in epiblasts are reduced in Frs2α-null embryos. These experiments underscore the critical role of FRS2α in mediating multiple processes during embryonic development and reveal a potential new link between FGF and Bmp4 signaling pathways in early embryogenesis.

ACKNOWLEDGMENTS

We thank X. Sun and G. R. Martin for helping in the sectioning of embryos and for valuable advice. We are thankful to L. Corson for the protocol of whole-mount immunohistochemistry with anti-phospho ERK antibodies. We thank A. Auerbach and staff members in Transgenic Animal Facility of NYU for making chimeric embryos. We are grateful to J. Rossant for critical readings of the manuscript and providing the probes, to V. P. Eswarakumar for critical readings of the manuscript, and to G. R. Martin, A. L. Joyner, and M. M. Shen for providing the probes.

N.G. was a recipient of Long Term Fellowship of Human Frontier Science Organization and Research Fellowship of Uehara Memorial Foundation during the early stages of the study. During the late stages of the study, this work was supported by Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture, Japan, to N.G. and M.S. Joseph Schlessinger is supported by NIH grants RO1-AR051448-01 and RO1-AR051886-01 and funds from the Ludwig Institute for Cancer Research.