P16 was first identified as a gene that was upregulated in mice deficient for NR3A (a novel NMDA receptor subunit; Tu et al., 2003, SfN abstract 796.2). We showed previously that forced expression of p16 in cultured hippocampal neurons resulted in increased PSD-95 clustering and enhanced dendritic-spine density. In the current study, we examined the functional diversity among p16 homologues. p16 is a member of a large gene family, and its variants show sequence diversity at the C-terminus. Due to these variations, some p16 members are predicted to bind PDZ domain-containing proteins, such as PSD-95, while others do not. We first tested this idea by co-expressing p16 or select variants together with PSD-95 in COS cells. In these experiments, variations at the C-termini among the p16 variants produced differential binding to PDZ domains. We next examined two p16 variants (p16-svi, which binds to PSD-95, and p16-svk, which does not) for their ability to cluster PSD-95 and increase dendritic spine density. We ...