Mammalian MutS homologue 5 is required for chromosome pairing in meiosis

MSH5 (MutS homologue 5) is a member of a family of proteins known to be involved in DNA mismatch repair(1,2). Germline mutations in MSH2, MLH1 and GTBP (also known as MSH6) cause hereditary non-polyposis colon cancer (HNPCC) or Lynch syndrome(3-8). Inactivation of Msh2, Mlh1, Gtmbp (also known as Msh6) or Pms2 in mice leads to hereditary predisposition to intestinal and other cancers(9-14). Early studies in yeast revealed a role for some of these proteins, including Msh5, in meiosis(15-17). Gene targeting studies in mice confirmed roles for Mlh1 and Pms2 in mammalian meiosis(12-14,18). To assess the role of Msh5 in mammals, we generated and characterized mice with a null mutation in Msh5 Msh5(-/-) mice are viable but sterile. Meiosis in these mice is affected due to the disruption of chromosome pairing in prophase I. We found that this meiotic failure leads to a diminution in testicular size and a complete loss of ovarian structures, Our results show that normal Msh5 function is essential for meiotic progression and, in females, gonadal maintenance.