The C terminus of p73 is essential for hippocampal development

Significance Alteration of splicing is emerging as a relevant cause of human disease. The C-terminal region of p73 is subject to complex alternative splicing that can give rise to seven different isoforms. Here, using a newly generated mouse model, we determine the functional consequence of in vivo ectopic switch from the physiologically expressed and most abundant isoform p73α to the shorter p73β isoform. Expression of p73β leads to neurodevelopmental defects with functional and morphological abnormalities in the mouse hippocampus. The ectopic isoform switch results in depletion of Cajal–Retzius (CR) neurons in embryonic stages, leading to aberrant hippocampal architecture. Our study indicates that deregulation in p73 alternative splicing might underlie neurodevelopmental human conditions.
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 α motif) from the Trp73 gene, we selectively engineered mice to replace the most abundantly expressed C-terminal isoform, p73α, with a shorter product of alternative splicing, p73β. These mice (Trp73Δ13/Δ13) display severe neurodevelopmental defects with significant functional and morphological abnormalities. Replacement of p73α with p73β 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, Trp73Δ13/Δ13 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.