Characterization of the roles of Fgfr2 in developmental branching morphogenesis and cardiovascular health.

摘要

Spontaneous mutations arise at a high rate in mice due in part to the high rate of endogenous retroviral insertions, and some percentage of these insertions result in mutant phenotypes. The recombinant inbred mouse strain CXB5 harbors a spontaneous recessive mutation called seminal vesicle shape (svs). These mice are viable and fertile, but they display defects in branching morphogenesis of the prostate and seminal vesicles.; To map the svs mutation a mouse cross was completed. Molecular and phenotypic analysis of the progeny from this cross identified a candidate interval of 400 kilobase pairs on mouse chromosome 7, a region syntenic with human chromosome 10. The svs mutation candidate interval contained two known genes, Fgfr2 and U6 snRNA, as well as six predicted genes. Sequencing, real time PCR, and restriction fragment length polymorphism Southern analysis identified an insertion of an MLV LTR in an intron of Fgfr2 . This insertion was subsequently found to be the causative mutation for the phenotypes observed in the svs mutant mice by altering the Fgfr2 isoform expression.; Following the identification of Fgfr2 as the affected gene in svs mutant mice, a series of studies of the role of Fgfr2 in developmental branching morphogenesis were initiated. Using synthetic inhibitors to FGFRs and the downstream MEK1/2-ERK1/2 signaling pathway, prostate bud induction was examined using in vitro organ cultures. Activation of both FGFRs and MEK1/2-ERK1/2 are required for normal prostatic bud induction. Loss of activation of either of these factors also resulted in a reversal of the androgen induced gene expression changes in branching morphogenesis regulators Fgf10, Bmp4, Bmp7, and Ptc1.; During the course of study, 7/42 homozygous svs mutant mice died before 12 months of age. Additional studies revealed that all svs mutant mice develop heart failure due to dilated cardiomyopathy with advancing age, although at three weeks of age svs mutant mice have completely normal heart morphology and function as assessed by echocardiography. Combined, the molecular analysis and characterization of the phenotypes present in the svs mutant mice have contributed significantly to the current understanding of prostate branching morphogenesis and the development of heart failure.