GENETIC RESCUE OF SEGMENTATION DEFECT IN MESP2-DEFICIENT MICE BY MESP1 GENE REPLACEMENT

Gene knock-out and knock-in strategies are employed to investigate the function of MesP1. MesP1 belongs to the same family of bHLH transcrip tion factors as MesP2. The early expression pattern observed in the ea rly mesoderm at the onset of gastrulation is restricted to Mesp1, whil e the later expression pattern in the anterior presomitic mesoderm dur ing somitogenesis is almost the same for Mesp1 as for Mesp2. Homozygou s Mesp1 null mice exhibited growth retardation after 7.5 dpc and died before 10.5 dpc with many developmental defects. The function of MesP1 during somitogenesis was not clearly revealed because of their early death and the possible compensation by MesP2. In order to examine the functions of MesP1 during somitogenesis, we replaced the Mesp2 gene wi th Mesp1 cDNA, using a gene knock-in strategy. The introduced Mesp1 cD NA could rescue the defects caused by Mesp2 deficiency in a dosage-dep endent manner. Mice which lacked Mesp2 expression but had four copies of the Mesp1 gene survived into the adulthood and were fertile. The sk eletal defects and the reduction in expression of Notch1, Notch2 and F GFR-1 previously observed in Mesp2 null mice were almost completely re scued by the introduced MesP1. Thus, it is concluded that the function s of MesP1 during somitogenesis, like MesP2, are also mediated via not ch-delta and FGF signaling systems. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.