A Pro-Apoptotic Fragment of the p75 Neurotrophin Receptor Is Expressed in p75NTR ExonIV Null Mice

• Published in: The Journal of neuroscience 2004-02, Vol.24 (8), p.1917-1923
• Main Authors: Paul, Christine E., Vereker, Emily, Dickson, Kathleen M., Barker, Philip A.
• Format: Article
• Language: English
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.5397-03.2004

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.