title: The Ras-like protein R-Ras2/TC21 is important for proper mammary gland development.
abstract: R-Ras2/TC21 is a GTPase with high sequence and signaling similarity with Ras subfamily members. Although it has been extensively studied using overexpression studies in cell lines, its physiological role remains poorly characterized. Here we used RRas2-knockout mice expressing β-galactosidase under the regulation of the endogenous RRas2 promoter to investigate the function of this GTPase in vivo. Despite its expression in tissues critical for organismal viability, RRas2(-/-) mice show no major alterations in viability, growth rates, cardiovascular parameters, or fertility. By contrast, they display a marked and specific defect in the development of the mammary gland during puberty. In the absence of R-Ras2/TC21, this gland forms reduced numbers of terminal end buds (TEBs) and ductal branches, leading to a temporal delay in the extension and arborization of the gland tree in mammary fat pads. This phenotype is linked to cell-autonomous proliferative defects of epithelial cells present in TEBs. These cells also show reduced Erk activation but wild type-like levels of phosphorylated Akt. Using compound RRas2-, HRas-, and NRas-knockout mice, we demonstrate that these GTPases act in a nonsynergistic and nonadditive manner during this morphogenic process.
authors.affiliation: Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas-University of Salamanca, E37007 Salamanca, Spain.
authors.forename: Romain M
authors.initials: RM
authors.lastname: Larive
authors.forename: Antonio
authors.initials: A
authors.lastname: Abad
authors.forename: Clara M
authors.initials: CM
authors.lastname: Cardaba
authors.forename: Teresa
authors.initials: T
authors.lastname: Hernández
authors.forename: Marta
authors.initials: M
authors.lastname: Cañamero
authors.forename: Enrique
authors.initials: E
authors.lastname: de Álava
authors.forename: Eugenio
authors.initials: E
authors.lastname: Santos
authors.forename: Balbino
authors.initials: B
authors.lastname: Alarcón
authors.forename: Xosé R
authors.initials: XR
authors.lastname: Bustelo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008321:Mammary Glands, Animal / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D001616:beta-Galactosidase; C490200:Rras2 protein, mouse; D020559:Monomeric GTP-Binding Proteins; D018631:ras Proteins