The C terminus of p73 is essential for hippocampal development

The p53 family member p73 has a complex gene structure, including alternative promoters and alternative splicing of the 3' UTR. This results in a complex range of isoforms whose biological relevance largely remains to be determined. By deleting exon 13 (which encodes a sterile alpha motif) from the Trp73 gene, we selectively engineered mice to replace the most abundantly expressed C-terminal isoform, p73 alpha, with a shorter product of alternative splicing, p730. These mice (Trp73(Delta 13/)(Delta)(13)) display severe neurodevelopmental defects with significant functional and morphological abnormalities. Replacement of p73 alpha with p73 beta results in the depletion of Cajal-Retzius (CR) cells in embryonic stages, thus depriving the developing hippocampus of the pool of neurons necessary for correct hippocampal architecture. Consequently, Trp73(Delta 13/)(Delta)(13) mice display severe hippocampal dysgenesis, reduced synaptic functionality and impaired learning and memory capabilities. Our data shed light on the relevance of p73 alternative splicing and show that the full-length C terminus of p73 is essential for hippocampal development.