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author:("rosier, Moira")
1.  The Tissue-Specific RNA Binding Protein T-STAR Controls Regional Splicing Patterns of Neurexin Pre-mRNAs in the Brain 
PLoS Genetics  2013;9(4):e1003474.
The RNA binding protein T-STAR was created following a gene triplication 520–610 million years ago, which also produced its two parologs Sam68 and SLM-1. Here we have created a T-STAR null mouse to identify the endogenous functions of this RNA binding protein. Mice null for T-STAR developed normally and were fertile, surprisingly, given the high expression of T-STAR in the testis and the brain, and the known infertility and pleiotropic defects of Sam68 null mice. Using a transcriptome-wide search for splicing targets in the adult brain, we identified T-STAR protein as a potent splicing repressor of the alternatively spliced segment 4 (AS4) exons from each of the Neurexin1-3 genes, and exon 23 of the Stxbp5l gene. T-STAR protein was most highly concentrated in forebrain-derived structures like the hippocampus, which also showed maximal Neurexin1-3 AS4 splicing repression. In the absence of endogenous T-STAR protein, Nrxn1-3 AS4 splicing repression dramatically decreased, despite physiological co-expression of Sam68. In transfected cells Neurexin3 AS4 alternative splicing was regulated by either T-STAR or Sam68 proteins. In contrast, Neurexin2 AS4 splicing was only regulated by T-STAR, through a UWAA-rich response element immediately downstream of the regulated exon conserved since the radiation of bony vertebrates. The AS4 exons in the Nrxn1 and Nrxn3 genes were also associated with distinct patterns of conserved UWAA repeats. Consistent with an ancient mechanism of splicing control, human T-STAR protein was able to repress splicing inclusion of the zebrafish Nrxn3 AS4 exon. Although Neurexin1-3 and Stxbp5l encode critical synaptic proteins, T-STAR null mice had no detectable spatial memory deficits, despite an almost complete absence of AS4 splicing repression in the hippocampus. Our work identifies T-STAR as an ancient and potent tissue-specific splicing regulator that uses a concentration-dependent mechanism to co-ordinately regulate regional splicing patterns of the Neurexin1-3 AS4 exons in the mouse brain.
Author Summary
Alternative splicing plays a key role in animal development and is largely controlled by the expression of RNA binding proteins. Most RNA binding proteins exist as families of sister proteins called paralogs, which result from gene amplification, including T-STAR, which is closely related to Sam68 and SLM-1. T-STAR, Sam68, and SLM-1 usually behave identically in splicing control in transfected cells. Here we report the physiological functions of T-STAR protein by knocking its parent gene out in the mouse. Surprisingly we observed no defects in germ cell maturation without T-STAR protein, an unexpected result given T-STAR protein is mainly expressed in the testis and its paralog Sam68 is essential for male fertility. Instead, we find T-STAR controls a panel of splicing targets that encode important synaptic proteins. T-STAR acts as a potent splicing repressor to establish regional splicing patterns of these target exons in the brain. Forebrain-derived structures like the hippocampus strongly express T-STAR protein to repress these target exons. Some T-STAR regulated splicing targets overlap with Sam68, but T-STAR also regulates its own distinct targets. Comparative genomic analyses are consistent with an ancient mechanism of splicing control by T-STAR that has been conserved since the radiation of bony vertebrates.
doi:10.1371/journal.pgen.1003474
PMCID: PMC3636136  PMID: 23637638
2.  Expression of PLA2G6 in human fetal development: Implications for infantile neuroaxonal dystrophy 
Brain research bulletin  2010;83(6):374-379.
Mutations in PLA2G6, which encodes calcium-independent phospholipase A2 group VIA (iPLA2-VIA), underlie the autosomal recessive disorder infantile neuroaxonal dystrophy (INAD). INAD typically presents in the first year of life, and leads to optic atrophy and psychomotor regression. We have examined PLA2G6 expression in early human embryonic development by in situ hybridization. At Carnegie Stage (CS) 19 (approximately 7 post conception weeks [PCW]), strong expression is evident in the ventricular zone (VZ) of midbrain and forebrain suggestive of expression in neural stem and progenitor cells. At CS23 (8 PCW) expression is also detectable in the VZ of the hindbrain and the subventricular zone (SVZ) of the developing neocortex, ganglionic eminences and diencephalon. By 9 PCW strong expression in the post-mitotic cells of the cortical plate can be seen in the developing neocortex. In the eye, expression is seen in the lens and retina at all stages examined. PLA2G6 expression is also evident in the alar plate of the spinal cord, dorsal root ganglia, the retina and lens in the eye and and several non-neuronal tissues, including developing bones, lung, kidney and gut. These findings suggest a role for PLA2G6 in neuronal proliferation throughout the developing brain and in maturing neurons in the cortical plate and hindbrain. Although widespread PLA2G6 expression is detected in neuronal tissues, the pattern shows dynamic changes with time and indicates that INAD pathogenesis may begin prior to birth.
doi:10.1016/j.brainresbull.2010.08.011
PMCID: PMC2975838  PMID: 20813170
PLA2G6; INAD; neurodegeneration; development; in-situ hybridization
3.  Human CHN1 mutations hyperactivate α2-chimaerin and cause Duane’s retraction syndrome 
Science (New York, N.Y.)  2008;321(5890):839-843.
The RacGAP molecule α2-chimaerin is implicated in neuronal signaling pathways required for precise guidance of developing corticospinal axons. We now demonstrate that a variant of Duane’s retraction syndrome, a congenital eye movement disorder in which affected individuals show aberrant development of axon projections to the extraocular muscles, can result from gain-of-function heterozygous missense mutations in CHN1 that increase α2-chimaerin RacGAP activity in vitro. A subset of mutations enhances α2-chimaerin membrane translocation and/or α2-chimaerin’s previously unrecognized ability to form a complex with itself. In ovo expression of mutant CHN1 alters the development of ocular motor axons. These data demonstrate that human CHN1 mutations can hyperactivate α2-chimaerin and result in aberrant cranial motor neuron development.
doi:10.1126/science.1156121
PMCID: PMC2593867  PMID: 18653847

Results 1-3 (3)