Cdk4 Conditional Knockout mouse — Foxp3-CreERT2 pairing

Cdk4, mouse ortholog of human CDK4, encodes the D-cyclin dependent kinase that initiates RB phosphorylation at the restriction point, is directly inhibited by the INK4 proteins p16, p15, p18 and p19 through an allosteric interface that distorts the ATP site, and requires assembly with p21 or p27 plus CAK activation to function. The R24C substitution abolishes INK4 binding and yields an INK4-insensitive kinase, and the homologous human R24C and R24H alleles cause familial melanoma, so an R24C knockin is the appropriate tool for testing whether tumors depend on INK4 restraint or on CDK4/6 inhibitor binding. Null mice are viable but diabetic from beta cell hypoplasia and infertile, making constitutive alleles usable while conditional designs isolate tissue requirement. Cdk6 substitutes broadly, particularly in hematopoietic lineages, so single deletion understates dependency and palbociclib class resistance studies need compound alleles. Select nulls for dependency mapping, R24C knockins for oncogenic drive, and pair conditional alleles with a lineage-matched Cre.

Cdk4 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. For regulatory T cell work, plan Cre specificity, reporter crosses, and baseline phenotyping before you scale.