Neuronal-Specific Deficiency of the Splicing Factor <i>Tra2b</i> Causes Apoptosis in Neurogenic Areas of the Developing Mouse Brain

<div><p>Alternative splicing (AS) increases the informational content of the genome and is more prevalent in the brain than in any other tissue. The splicing factor <i>Tra2b</i> (<i>Sfrs10</i>) can modulate splicing inclusion of exons by specifically detecting GAA-rich binding motifs and its absence causes early embryonic lethality in mice. <i>TRA2B</i> has been shown to be involved in splicing processes of <i>Nasp</i> (nuclear autoantigenic sperm protein), <i>MAPT</i> (microtubule associated protein tau) and <i>SMN</i> (survival motor neuron), and is therefore implicated in spermatogenesis and neurological diseases like Alzheimer’s disease, dementia, Parkinson’s disease and spinal muscular atrophy. Here we generated a <i>neuronal</i>-specific <i>Tra2b</i> knock-out mouse that lacks <i>Tra2b</i> expression in neuronal and glial precursor cells by using the <i>Nestin-Cre</i>. Neuronal-specific <i>Tra2b</i> knock-out mice die immediately after birth and show severe abnormalities in cortical development, which are caused by massive apoptotic events in the ventricular layers of the cortex, demonstrating a pivotal role of Tra2b for the developing central nervous system. Using whole brain RNA on exon arrays we identified differentially expressed alternative exons of <i>Tubulinδ1</i> and <i>Shugoshin-like2</i> as <i>in vivo</i> targets of Tra2b. Most interestingly, we found increased expression of the cyclin dependent kinase inhibitor 1a (p21) which we could functionally link to neuronal precursor cells in the affected brain regions. We provide further evidence that the absence of <i>Tra2b</i> causes <i>p21</i> upregulation and ultimately cell death in NSC34 neuronal-like cells. These findings demonstrate that <i>Tra2b</i> regulates splicing events essential for maintaining neuronal viability during development. Apoptotic events triggered via <i>p21</i> might not be restricted to the developing brain but could possibly be generalized to the whole organism and explain early embryonic lethality in <i>Tra2b</i>-depleted mice.</p>