NRIF (neurotrophin receptor interacting factor) is a ubiquitously expressed zinc finger protein of the Krüppel family which interacts with the neurotrophin receptor p75(NTR). The interaction was first detected in yeast and then biochemically confirmed using recombinant GST-NRIF fusions and p75(NTR) expressed by eukaryotic cells. Transgenic mice carrying a deletion in the exon encoding the p75(NTR)-binding domain of NRIF display a phenotype which is strongly dependent upon genetic background. While at the F(2 )generation there is only limited (20%) embryonic lethality, in a congenic BL6 strain nrif(-/-) mice cannot survive beyond E12, but are viable and healthy to adulthood in the Sv129 background. The involvement of NRIF in p75(NTR)/NGF-mediated developmental cell death was examined in the mouse embryonic neural retina. Disruption of the nrif gene leads to a reduction in cell death which is quantitatively indistinguishable from that observed in p75(NTR)(-/-) and ngf(-/-) mice. These results indicate that NRIF is an intracellular p75(NTR)-binding protein transducing cell death signals during development.