A Pro-Apoptotic Fragment of the p75 Neurotrophin Receptor Is Expressed in p75NTRExonIV Null Mice

• Published in: The Journal of neuroscience Vol. 24; no. 8; pp. 1917 - 1923
• Main Authors: Paul, Christine E, Vereker, Emily, Dickson, Kathleen M, Barker, Philip A
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 25.02.2004; Society for Neuroscience
• Subjects: Animals; Apoptosis - genetics; Base Sequence; Brief Communications; Caspase 3; Caspases - metabolism; Cells, Cultured; Exons - genetics; Heterozygote; Homozygote; Humans; Kidney - cytology; Kidney - metabolism; Mice; Mice, Knockout; Mice, Mutant Strains; Molecular Sequence Data; Nervous System Diseases - genetics; PC12 Cells; Peptide Fragments - biosynthesis; Peptide Fragments - genetics; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Rats; Receptor, Nerve Growth Factor; Receptors, Nerve Growth Factor - biosynthesis; Receptors, Nerve Growth Factor - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - biosynthesis; Signal Transduction - genetics; Transcription, Genetic - genetics; Transfection; Vascular Diseases - genetics
• 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 (p75NTRExonIV-/-), whereas mice lacking p75NTR Exon III (p75NTRExonIII-/-) maintain expression of an alternatively spliced form of p75NTR (s-p75NTR). Here, we report that p75NTRExonIV-/- 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 p75NTRExonIV-/- phenotype may reflect a gain-of-function mutation rather than loss of p75NTR function.