Mlh1 Conditional Knockout mouse models

Mlh1, the mouse ortholog of human MLH1, encodes the obligate partner of the MutL family, dimerizing with Pms2 to form MutLalpha, and less commonly with Mlh3 or Pms1; recruited by mismatch-bound MutSalpha, the complex uses ATP binding and the latent Pms2 endonuclease to nick the nascent strand, licensing Exo1-mediated excision and resynthesis, and it separately cooperates with Mlh3 to resolve meiotic recombination intermediates into crossovers. Germline loss causes Lynch syndrome with microsatellite instability, and somatic promoter hypermethylation silences it in sporadic colorectal and endometrial cancer. Homozygous nulls are viable but cancer-prone and sterile from meiotic failure, so conditional alleles are the way to study tissue-restricted repair loss without confounding infertility. Endonuclease-dead and dimerization-selective knockins separate repair from crossover functions, while humanization enables functional classification of variants of uncertain significance. Mlh3 and Pms1 partially cover meiotic roles but cannot substitute for MutLalpha in repair, so compensation is limited.

Mlh1 conditional knockout mice carry a floxed allele so you delete function only where Cre is active. The germline allele stays intact until you cross to a tissue specific Cre. Labs reach for this design when a global knockout is lethal, when they need adult onset loss, or when regional redundancy hides a whole body phenotype.