title: Neuronal-specific deficiency of the splicing factor Tra2b causes apoptosis in neurogenic areas of the developing mouse brain.
abstract: 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 Tra2b (Sfrs10) can modulate splicing inclusion of exons by specifically detecting GAA-rich binding motifs and its absence causes early embryonic lethality in mice. TRA2B has been shown to be involved in splicing processes of Nasp (nuclear autoantigenic sperm protein), MAPT (microtubule associated protein tau) and SMN (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 neuronal-specific Tra2b knock-out mouse that lacks Tra2b expression in neuronal and glial precursor cells by using the Nestin-Cre. Neuronal-specific Tra2b 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 Tubulinδ1 and Shugoshin-like2 as in vivo 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 Tra2b causes p21 upregulation and ultimately cell death in NSC34 neuronal-like cells. These findings demonstrate that Tra2b regulates splicing events essential for maintaining neuronal viability during development. Apoptotic events triggered via p21 might not be restricted to the developing brain but could possibly be generalized to the whole organism and explain early embryonic lethality in Tra2b-depleted mice.
authors.affiliation: Institute of Human Genetics, University of Cologne, Cologne, Germany ; Institute of Genetics, University of Cologne, Cologne, Germany ; Center for Molecular Medicine, University of Cologne, Cologne, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Storbeck
authors.affiliation: Institute of Human Genetics, University of Cologne, Cologne, Germany ; Institute of Genetics, University of Cologne, Cologne, Germany ; Center for Molecular Medicine, University of Cologne, Cologne, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Hupperich
authors.affiliation: Insitute of Neurophysiology, University of Cologne, Cologne, Germany.
authors.forename: John Antonydas
authors.initials: JA
authors.lastname: Gaspar
authors.affiliation: Insitute of Neurophysiology, University of Cologne, Cologne, Germany.
authors.forename: Kesavan
authors.initials: K
authors.lastname: Meganathan
authors.affiliation: Institute of Human Genetics, University of Cologne, Cologne, Germany ; Institute of Genetics, University of Cologne, Cologne, Germany ; Center for Molecular Medicine, University of Cologne, Cologne, Germany.
authors.forename: Lilian
authors.initials: L
authors.lastname: Martínez Carrera
authors.affiliation: Institute of Human Genetics, University of Cologne, Cologne, Germany.
authors.forename: Radu
authors.initials: R
authors.lastname: Wirth
authors.affiliation: Insitute of Neurophysiology, University of Cologne, Cologne, Germany.
authors.forename: Agapios
authors.initials: A
authors.lastname: Sachinidis
authors.affiliation: Institute of Human Genetics, University of Cologne, Cologne, Germany ; Institute of Genetics, University of Cologne, Cologne, Germany ; Center for Molecular Medicine, University of Cologne, Cologne, Germany.
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Wirth
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001921:Brain / Q000196:embryology* / Q000378:metabolism*; D002478:Cells, Cultured; D020964:Embryo Loss / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000502:physiology; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011247:Pregnancy; D012326:RNA Splicing / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors
chemical_list: D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C100345:Tra2b protein, mouse; D000068103:Serine-Arginine Splicing Factors