A pro-apoptotic fragment of the p75 neurotrophin receptor is expressed in p75NTRExonIV null mice

The p75 neurotrophin receptor (p75NTR) regulates neuronal survival, apoptosis, and growth. Recent studies have reported that disruption of Exon IV produces a null mouse lacking all p75NTR gene products (p75NTR(ExonIV-/-)), whereas mice lacking p75NTR Exon III (p75NTR(ExonIII-/-)) maintain expression of an alternatively spliced form of p75NTR (s-p75NTR). Here, we report that p75NTR(ExonIV-/-) mice express a p75NTR gene product that encodes a truncated protein containing the extracellular stalk region together with the entire transmembrane and intracellular domains. The gene product is initiated from a cryptic Kozak consensus/initiator ATG sequence within a region of Exon IV located 3' to the pGK-Neo insertion site. Overexpression of this fragment in heterologous cells results in activation of Jun kinase and induces Pro-caspase- 3 cleavage, indicating that it activates p75NTR signaling cascades. These results indicate that aspects of the p75NTR(ExonIV-/-) phenotype may reflect a gain-of-function mutation rather than loss of p75NTR function.