Interaction of the BMPR-IA tumor suppressor with a developmentally relevant splicing factor

Nishanian, Tagvor G.; Waldman, Todd

doi:10.1016/j.bbrc.2004.08.060

Cited by 27 publications

(19 citation statements)

References 23 publications

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“…Sf3b4 was isolated in a yeast two-hybrid screen as a factor interacting with the intracellular domain of BMP receptor IA (BMPR-IA; Nishanian and Waldman, 2004) and was shown to interfere with BMP activity in tissue culture (Watanabe et al, 2007). To address a potential function of Sf3b4 in BMP signaling we first analyzed by in situ hybridization the consequences of Sf3b4 depletion on msx1 expression, a direct BMP target (Suzuki et al, 1997).…”

Section: Resultsmentioning

confidence: 99%

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Sf3b4-depleted Xenopus embryos: A model to study the pathogenesis of craniofacial defects in Nager syndrome

Devotta

Juraver-Geslin

González

et al. 2016

Developmental Biology

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Mandibulofacial dysostosis (MFD) is a human developmental disorder characterized by defects of the facial bones. It is the second most frequent craniofacial malformation after cleft lip and palate. Nager syndrome combines many features of MFD with a variety of limb defects. Mutations in SF3B4 (splicing factor 3b, subunit 4) gene, which encodes a component of the pre-mRNA spliceosomal complex, were recently identified as a cause for Nager syndrome, accounting for 60% of affected individuals. Nothing is known about the cellular pathogenesis underlying Nager type MFD. Here we describe the first animal model for Nager syndrome, generated by knocking down Sf3b4 function in Xenopus laevis embryos, using morpholino antisense oligonucleotides. Our results indicate that Sf3b4-depleted embryos show reduced expression of the neural crest genes sox10, snail2 and twist at the neural plate border, associated with a broadening of the neural plate. This phenotype can be rescued by injection of wild-type human SF3B4 mRNA but not by mRNAs carrying mutations that cause Nager syndrome. At the tailbud stage, morphant embryos had decreased sox10 and tfap2a expression in the pharyngeal arches, indicative of a reduced number of neural crest cells. Later in development, Sf3b4-depleted tadpoles exhibited hypoplasia of neural crest-derived craniofacial cartilages, phenocopying aspects of the craniofacial skeletal defects seen in Nager syndrome patients. With this animal model we are now poised to gain important insights into the etiology and pathogenesis of Nager type MFD, and to identify the molecular targets of Sf3b4.

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Section: Resultsmentioning

confidence: 99%

“…Several years ago, Sf3b4 was isolated in a yeast two-hybrid screen as a factor that interacts with the intracellular domain of BMPR-IA (Nishanian and Waldman, 2004; Watanabe et al, 2007). In tissue culture, overexpression of Sf3b4 was shown to inhibit BMP2-mediated osteogenic and chondrocytic differentiation (Watanabe et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Sf3b4-depleted Xenopus embryos: A model to study the pathogenesis of craniofacial defects in Nager syndrome

Devotta

Juraver-Geslin

González

et al. 2016

Developmental Biology

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“…A question arising from our studies is if the dynamics and constituent components of this complex during pre-mRNA binding could be modified in response to BMP signalling. Of the known RBM39-interacting SR proteins, SF3B4/SAP49 can bind the type I BMP receptor BMPR1A/ALK346. Overexpression of SF3B4 also suppresses Id reporter activity and negatively regulates cell surface levels of BMPR1A47.…”

Section: Discussionmentioning

confidence: 99%

Negative autoregulation of BMP dependent transcription by SIN3B splicing reveals a role for RBM39

Faherty

Benson

Sharma

et al. 2016

Sci Rep

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BMP signalling is negatively autoregulated by several genes including SMAD6, Noggin and Gremlin, and autoregulators are possible targets for enhancing BMP signalling in disorders such as fibrosis and pulmonary hypertension. To identify novel negative regulators of BMP signalling, we used siRNA screening in mouse C2C12 cells with a BMP-responsive luciferase reporter. Knockdown of several splicing factors increased BMP4-dependent transcription and target gene expression. Knockdown of RBM39 produced the greatest enhancement in BMP activity. Transcriptome-wide RNA sequencing identified a change in Sin3b exon usage after RBM39 knockdown. SIN3B targets histone deacetylases to chromatin to repress transcription. In mouse, Sin3b produces long and short isoforms, with the short isoform lacking the ability to recruit HDACs. BMP4 induced a shift in SIN3B expression to the long isoform, and this change in isoform ratio was prevented by RBM39 knockdown. Knockdown of long isoform SIN3B enhanced BMP4-dependent transcription, whereas knockdown of the short isoform did not. We propose that BMP4-dependent transcription is negatively autoregulated in part by SIN3B alternative splicing, and that RBM39 plays a role in this process.

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“…The inhibitory effect of SF3b4 on cell differentiation may therefore be peculiar to osteochondrogenic cell lineages. Indeed, although SF3b4 directly binds BMPR-IA, its function has not been determined in other cell types (32). By in situ hybridization, SF3b4 is expressed at a high level in limbs and somites at embryonic day 11 (39), suggesting its involvement in skeletal development.…”

Section: Discussionmentioning

confidence: 99%

Splicing Factor 3b Subunit 4 Binds BMPR-IA and Inhibits Osteochondral Cell Differentiation

Watanabe

Shionyu

Kimura

et al. 2007

Journal of Biological Chemistry

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Interaction of the BMPR-IA tumor suppressor with a developmentally relevant splicing factor

Cited by 27 publications

References 23 publications

Sf3b4-depleted Xenopus embryos: A model to study the pathogenesis of craniofacial defects in Nager syndrome

Sf3b4-depleted Xenopus embryos: A model to study the pathogenesis of craniofacial defects in Nager syndrome

Negative autoregulation of BMP dependent transcription by SIN3B splicing reveals a role for RBM39

Splicing Factor 3b Subunit 4 Binds BMPR-IA and Inhibits Osteochondral Cell Differentiation

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