Cdkn2a Conditional Knockout mouse — Vav1-Cre pairing

Cdkn2a, the mouse ortholog of human CDKN2A, is unusual because a single locus encodes two unrelated tumor suppressors from alternative reading frames: p16INK4a, an ankyrin repeat protein that allosterically inhibits CDK4 and CDK6 to keep RB hypophosphorylated, and p19ARF (human p14ARF) from an alternate first exon, which sequesters MDM2 in the nucleolus to stabilize p53. Deletion of the entire locus therefore disables the RB and p53 axes simultaneously, which is why bulk 9p21 loss is among the most common events in melanoma, glioma, pancreatic cancer and mesothelioma but is uninterpretable for mechanism. Allele design must be isoform-specific: exon 1 alpha targeted alleles remove p16 alone, exon 1 beta targeted alleles remove ARF alone, and only the combined deletion mimics the human co-deletion. Cdkn2b lies adjacent, is frequently co-deleted, and p15 partially compensates for p16 loss. Match allele to endpoint, using p16-specific alleles for CDK4/6 inhibitor sensitivity and ARF-specific alleles for p53 pathway questions.

Cdkn2a 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 hematopoietic work, plan Cre specificity, reporter crosses, and baseline phenotyping before you scale.