Characterization of R-Ras3/M-Ras Null Mice Reveals a Potential Role in Trophic Factor Signaling

Abstract

R-Ras3/M-Ras is a member of the RAS superfamily of small-molecular-weight GTP-binding proteins. Previous studies have demonstrated high levels of expression in several regions of the central nervous system, and a constitutively active form of M-Ras promotes cytoskeletal reorganization, cellular transformation, survival, and differentiation. However, the physiological functions of M-Ras during embryogenesis and postnatal development have not been elucidated. By using a specific M-Ras antibody, we demonstrated a high level of M-Ras expression in astrocytes, in addition to neurons. Endogenous M-Ras was activated by several trophic factors in astrocytes, including epidermal growth factor (EGF), basic fibroblast growth factor, and hepatocyte growth factor. Interestingly, M-Ras activation by EGF was more sustained compared to prototypic Ras. A mouse strain deficient in M-Ras was generated to investigate its role in development. M-Ras null mice appeared phenotypically normal, and there was a lack of detectable morphological and neurological defects. In addition, primary astrocytes derived from Mras^−/− mice did not appear to display substantial alterations in the activation of both the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways in response to trophic factors.

Supplemental material for this article may be found at http://mcb.asm.org/.

We thank Cristina Alberini, Deanna Benson, Maria Diverse, Mitchell Goldfarb, Garrett John, Kevin Kelley, and Matthew Shapiro (Mt. Sinai) for invaluable advice and Paula Bos for technical assistance.

This study was funded by NIH grants MH59771 and CA78509 to A.M.-L.C. and an NCI Shared Resources grant (CA88302). A.C.K. is a recipient of the Leonard B. Holman Research Pathway fellowship. T.H. is supported by DOD IDEA award DAMD17-03-1-0682.