Msh2 Conditional Knockout mouse models

Msh2, the mouse ortholog of human MSH2, encodes the common subunit of both mismatch recognition complexes, pairing with Msh6 to form MutSalpha for base-base mispairs and small insertion or deletion loops and with Msh3 to form MutSbeta for larger loops; mismatch binding stimulates its Walker-motif ATPase, converting the heterodimer into a sliding clamp that recruits MutLalpha and licenses strand-specific excision, and the same machinery drives triplet repeat expansion and mediates the cytotoxicity of methylating agents. Germline biallelic loss causes constitutional mismatch repair deficiency and monoallelic loss causes Lynch syndrome, with microsatellite instability and hypermutation that confer immune checkpoint sensitivity. Nulls are viable, lymphoma-prone, and tolerant of temozolomide, so germline alleles are usable, while conditional deletion restricts hypermutation to a lineage of interest. ATPase separation-of-function knockins uncouple repair from damage signaling, and humanization supports variant classification. Msh6 and Msh3 are partners rather than substitutes, so no compensation rescues Msh2 loss.

Msh2 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.