Altered mRNA Splicing, Chondrocyte Gene Expression and Abnormal Skeletal Development due to SF3B4 Mutations in Rodriguez Acrofacial Dysostosis

Marques, Felipe Albuquerque; Tenney, Jessica; Durán, Iván; Martı́n, Jorge; Nevarez, Lisette; Pogue, Robert; Krakow, Deborah; Cohn, Daniel H.; Li, Bing

doi:10.1371/journal.pgen.1006307

Cited by 39 publications

(35 citation statements)

References 77 publications

(79 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One of the possibilities that cause this morphological change is that down‐regulation of Sf3b4 expression affects Sf3b1 expression level. However, the SF3B1 expression level is not significantly different in a patient of Rodriguez syndrome (heterozygous mutation of SF3B4 ) compared to control . Importantly, Isono et al have shown that SF3b4 forms a complex with Rnf2 and Zfp144 as Sf3b1 does.…”

Section: Discussionmentioning

confidence: 96%

See 1 more Smart Citation

Heterozygous mutation of the splicing factor Sf3b4 affects development of the axial skeleton and forebrain in mouse

Yamada

Takechi

Yokoyama

et al. 2020

Developmental Dynamics

View full text Add to dashboard Cite

Background: Splicing factor 3B subunit 4 (SF3B4) is a causative gene of an acrofacial dysostosis, Nager syndrome. Although in vitro analyses of SF3B4 have proposed multiple noncanonical functions unrelated to splicing, less information is available based on in vivo studies using model animals. Results:We performed expression and functional analyses of Sf3b4 in mice. The mouse Sf3b4 transcripts were found from two-cell stage, and were ubiquitously present during embryogenesis with high expression levels in several tissues such as forming craniofacial bones and brain. In contrast, expression of a pseudogene-like sequence of mouse Sf3b4 (Sf3b4_ps) found by in silico survey was not detected up to embryonic day 10. We generated a Sf3b4 knockout mouse using CRISPR-Cas9 system. The homozygous mutant mouse of Sf3b4 was embryonic lethal. The heterozygous mutant of Sf3b4 mouse (Sf3b4 +/− ) exhibited smaller body size compared to the wild-type from postnatal to adult period, as well as homeotic posteriorization of the vertebral morphology and flattened calvaria. The flattened calvaria appears to be attributable to mild microcephaly due to a lower cell proliferation rate in the forebrain. Conclusions:Our study suggests that Sf3b4 controls anterior-posterior patterning of the axial skeleton and guarantees cell proliferation for forebrain development in mice. K E Y W O R D Shomeotic posteriorization, microcephaly, Nager syndrome, splicing factor Takahiko Yamada and Masaki Takechi contributed equally to this study.

show abstract

Section: Discussionmentioning

confidence: 96%

“…A recent study using specimens of Rodriguez syndrome patients with haploinsufficiency of SF3B4 showed that mRNA splicing is altered in fetal chondrocytes . In contrast, an in vitro study reported that human SF3b4 regulates osteochondral differentiation by interacting with bone morphogenetic protein (BMP) receptor, BMPR‐I .…”

Section: Introductionmentioning

confidence: 99%

Heterozygous mutation of the splicing factor Sf3b4 affects development of the axial skeleton and forebrain in mouse

Yamada

Takechi

Yokoyama

et al. 2020

Developmental Dynamics

View full text Add to dashboard Cite

show abstract

“…Devotta et al () found that some genes involved in NCC development were down‐regulated, however, they did not find evidence to support the hypothesis that the down‐regulation of these genes was associated with defective splicing. In contrast, a recent study by Marques et al () in human tissue showed that mRNA splicing is impaired in chondrocytes of fetuses with Rodriguez syndrome, which is a more severe and lethal form of Nager syndrome that is also caused by mutations in SF3B4 . SF3B4 has also been reported to bind to BMPR‐IA and inhibit BMP‐mediated osteochondral cell differentiation, which may also contribute to skeletal defects (Nishanian and Waldman, ; Watanabe, Shionyu, Kimura, Kimata, & Watanabe, ).…”

Section: Developmental Processes Linking Spliceosomopathies and Ribosmentioning

confidence: 86%

Developmental processes regulate craniofacial variation in disease and evolution

Merkuri

Fish

2018

Genesis

View full text Add to dashboard Cite

Variation in development mediates phenotypic differences observed in evolution and disease. Although the mechanisms underlying phenotypic variation are still largely unknown, recent research suggests that variation in developmental processes may play a key role. Developmental processes mediate genotype-phenotype relationships and consequently play an important role regulating phenotypes. In this review, we provide an example of how shared and interacting developmental processes may explain convergence of phenotypes in spliceosomopathies and ribosomopathies. These data also suggest a shared pathway to disease treatment. We then discuss three major mechanisms that contribute to variation in developmental processes: genetic background (gene-gene interactions), gene-environment interactions, and developmental stochasticity. Finally, we comment on evolutionary alterations to developmental processes, and the evolution of disease buffering mechanisms.

show abstract

“…Among these selected RNA binding proteins, we included factors that are core splicing factors but which also have been shown to alter alternative splicing. These include U2AF1, U2AF2, SF3A3, and SF3B4 [53][54][55][56][57]. Out of these 27 unique eCLIP assayed factors, 16 splicing regulators were also studied in both cell lines.…”

Section: Extensive Rust Revealed By a Splicing Factor Interaction Netmentioning

confidence: 99%

Networks of Splice Factor Regulation by Unproductive Splicing Coupled With Nonsense Mediated mRNA Decay

Desai

French

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Nonsense mediated mRNA decay (NMD) is an RNA surveillance pathway that degrades aberrant transcripts harboring premature termination codons. This pathway, in conjunction with alternative splicing, regulates gene expression post-transcriptionally. Nearly all serine and arginine-rich (SR) proteins and many heterogeneous nuclear ribonucleoproteins (hnRNPs) produce isoforms that can be degraded by the NMD pathway. Many splicing factors have been reported to be regulated via alternative splicing coupled to NMD. However, it is still uncharacterized that to what extent NMD contributes to the regulation of splicing factors.Results: Here, we characterized a regulatory network of splicing factors through alternative splicing coupled to NMD. Based upon an extensive literature search, we first assembled a network that encompasses the current knowledge of splice factors repressing or activating the expression of other splicing factors through alternative splicing coupled to NMD. This regulatory network is limited, including just a handful of well-studied splicing factors. To gain a more global and less biased overview, we examined the splicing factor-mRNA interactions from public crosslinking-immunoprecipitation (CLIP)-seq data, which provides information about protein-RNA interactions. A network view of these interactions reveals extensive binding among splicing regulators. We also found that splicing factors bind more frequently to transcripts of other splicing factors than to other genes. In addition, many splicing factors are targets of NMD, and might be regulated via alternative splicing coupled to NMD, which is demonstrated by the significant overlap between the experimental network and eCLIP-network. We found that hierarchy of the splicing-factor interaction network differs from the hierarchy observed for transcription factors. Conclusion:The extensive interaction between splicing factors and transcripts of other splicing factors suggests that the potential regulation via alternative splicing coupled with NMD is widespread. The splicing factor regulation is fundamentally different from that of transcription factors.

show abstract

Altered mRNA Splicing, Chondrocyte Gene Expression and Abnormal Skeletal Development due to SF3B4 Mutations in Rodriguez Acrofacial Dysostosis

Cited by 39 publications

References 77 publications

Heterozygous mutation of the splicing factor Sf3b4 affects development of the axial skeleton and forebrain in mouse

Heterozygous mutation of the splicing factor Sf3b4 affects development of the axial skeleton and forebrain in mouse

Developmental processes regulate craniofacial variation in disease and evolution

Networks of Splice Factor Regulation by Unproductive Splicing Coupled With Nonsense Mediated mRNA Decay

Contact Info

Product

Resources

About