Figure 7.

Splicing mechanisms of p53 anti-repression and motor neuron death in SMA. Schematic summary of the molecular cascade initiated by SMN deficiency, followed by reduction in the levels of spliceosomal snRNPs of the major spliceosome and consequent dysregulation of Mdm2 exon 3 and Mdm4 exon 7 alternative splicing, resulting in their increased skipping. Dysregulation of both splicing events is required to synergistically induce p53 stabilization, which is the initiating step in the death pathway leading to motor neuron loss in SMA mice. See the text for additional details.