title: Targeted disruption of Ras-Grf2 shows its dispensability for mouse growth and development.
abstract: The mammalian Grf1 and Grf2 proteins are Ras guanine nucleotide exchange factors (GEFs) sharing a high degree of structural homology, as well as an elevated expression level in central nervous system tissues. Such similarities raise questions concerning the specificity and/or redundancy at the functional level between the two Grf proteins. grf1-null mutant mice have been recently described which showed phenotypic growth reduction and long-term memory loss. To gain insight into the in vivo function of Grf2, we disrupted its catalytic CDC25-H domain by means of gene targeting. Breeding among grf2(+/-) animals gave rise to viable grf2(-/-) adult animals with a normal Mendelian pattern, suggesting that Grf2 is not essential for embryonic and adult mouse development. In contrast to Grf1-null mice, analysis of grf2(-/-) litters showed similar size and weight as their heterozygous or wild-type grf2 counterparts. Furthermore, adult grf2(-/-) animals reached sexual maturity at the same age as their wild-type littermates and showed similar fertility levels. No specific pathology was observed in adult Grf2-null animals, and histopathological studies showed no observable differences between null mutant and wild-type Grf2 mice. These results indicate that grf2 is dispensable for mouse growth, development, and fertility. Furthermore, analysis of double grf1/grf2 null animals did not show any observable phenotypic difference with single grf1(-/-) animals, further indicating a lack of functional overlapping between the two otherwise highly homologous Grf1 and Grf2 proteins.
authors.affiliation: Centro de Investigación del Cáncer, IBMCC, CSIC-USAL, University of Salamanca, 37007 Salamanca, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Fernández-Medarde
authors.forename: Luis M
authors.initials: LM
authors.lastname: Esteban
authors.forename: Alejandro
authors.initials: A
authors.lastname: Núñez
authors.forename: Angel
authors.initials: A
authors.lastname: Porteros
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.forename: Eugenio
authors.initials: E
authors.lastname: Santos
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D005260:Female; D005298:Fertility; D018390:Gene Targeting; D006128:Growth; D006579:Heterozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D017434:Protein Structure, Tertiary; D012741:Sexual Maturation; D020663:ras Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D020666:ras-GRF1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology
chemical_list: C504491:Rasgrf2 protein, mouse; D020663:ras Guanine Nucleotide Exchange Factors; D020666:ras-GRF1