Universität zu Köln

Storbeck, Markus, Hupperich, Kristina, Gaspar, John Antonydas, Meganathan, Kesavan, Carrera, Lilian Martinez, Wirth, Radu, Sachinidis, Agapios and Wirth, Brunhilde ORCID: 0000-0003-4051-5191 (2014). Neuronal-Specific Deficiency of the Splicing Factor Tra2b Causes Apoptosis in Neurogenic Areas of the Developing Mouse Brain. PLoS One, 9 (2). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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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 Tubulind1 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Storbeck, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Hupperich, Kristina UNSPECIFIED UNSPECIFIED UNSPECIFIED Gaspar, John Antonydas UNSPECIFIED UNSPECIFIED UNSPECIFIED Meganathan, Kesavan UNSPECIFIED UNSPECIFIED UNSPECIFIED Carrera, Lilian Martinez UNSPECIFIED UNSPECIFIED UNSPECIFIED Wirth, Radu UNSPECIFIED UNSPECIFIED UNSPECIFIED Sachinidis, Agapios UNSPECIFIED UNSPECIFIED UNSPECIFIED Wirth, Brunhilde UNSPECIFIED orcid.org/0000-0003-4051-5191 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-445770
DOI:	10.1371/journal.pone.0089020
Journal or Publication Title:	PLoS One
Volume:	9
Number:	2
Date:	2014
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language VALPROIC ACID; EXON 10; HISTONE CHAPERONE; SEX DETERMINATION; RNA-RECOGNITION; TAU GENE; PROTEIN; EXPRESSION; TRA2-BETA; CELLS Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/44577