Dysregulation of Spliceosomes Complex Induces Retinitis Pigmentosa–Like Characteristics in sf3b4-Depleted Zebrafish

Ulhaq, Zulvikar Syambani; Okamoto, Keigo; Ogino, Yukiko; Tse, William Ka Fai

doi:10.1016/j.ajpath.2023.05.008

Cited by 11 publications

(3 citation statements)

References 52 publications

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“…The axial skeleton defects have been attributed to mis-splicing of chromatin remodelers and dysregulation of Hox gene expression (Kumar et al, 2023). In zebrafish, sf3b4 mutation causes massive cell death in the retina of the eye (Ulhaq et al, 2023), reminiscent of another spliceosomopathy, retinitis pigmentosa (Griffin and Saint-Jeannet, 2020). In Xenopus laevis , morpholino-induced knockdown of Sf3b4 led to a reduction in NC gene expression resulting in hypoplastic craniofacial cartilages, attributed to an increase in NCC apoptosis (Devotta et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Human stem cell model of neural crest cell differentiation reveals a requirement of SF3B4 in survival, maintenance, and differentiation

Griffin,

Saint-Jeannet

2024

Preprint

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In vitro modeling is a powerful approach to investigate the pathomechanisms driving human congenital conditions. Here we use human embryonic stem cells (hESCs) to model Nager and Rodriguez syndromes, two craniofacial conditions characterized by hypoplastic neural crest-derived craniofacial bones, caused by pathogenic variants of SF3B4, a core component of the spliceosome. We observed that siRNA-mediated knockdown of SF3B4 interferes with the production of hESC-derived neural crest cells, as seen by a marked reduction in neural crest gene expression. This phenotype is associated with an increase in neural crest cell apoptosis and their premature neuronal differentiation. Together, these results point at a role of SF3B4 in neural crest cell survival, maintenance, and differentiation as the primary cause of Nager/Rodriguez syndrome associated craniofacial defects, and illustrate the benefit of in vitro human stem cell models to understand congenital diseases.

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Section: Discussionmentioning

confidence: 99%

Human stem cell model of neural crest cell differentiation reveals a requirement of SF3B4 in survival, maintenance, and differentiation

Griffin,

Saint-Jeannet

2024

Preprint

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“…In total, 0.5 µg of RNA was reverse transcribed using Superscript VILO (Thermofisher, Waltham, MA, USA). Real-time PCR was conducted on the QuantStudio 3 Real-Time PCR system (Thermofisher) using Power SYBR ® Green PCR Master Mix (Thermofisher) and the primer sets listed in Table 1, as previously described [19][20][21]. Graphs and statistical analyses were conducted using GraphPad Prism 9.…”

Section: Methodsmentioning

confidence: 99%

PFHxS Exposure and the Risk of Non-Alcoholic Fatty Liver Disease

Ulhaq,

Tse

2024

Genes

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Perfluorohexanesulfonic acid (PFHxS) is a highly prevalent environmental pollutant, often considered to be less toxic than other poly- and perfluoroalkyl substances (PFASs). Despite its relatively lower environmental impact compared to other PFASs, several studies have suggested that exposure to PFHxS may be associated with disruptions of liver function in humans. Nevertheless, the precise pathomechanisms underlying PFHxS-induced non-alcoholic fatty liver disease (NAFLD) remain relatively unclear. Therefore, this study applied our previously published transcriptome dataset to explore the effects of PFHxS exposure on the susceptibility to NAFLD and to identify potential mechanisms responsible for PFHxS-induced NAFLD through transcriptomic analysis conducted on zebrafish embryos. Results showed that exposure to PFHxS markedly aggravated hepatic symptoms resembling NAFLD and other metabolic syndromes (MetS) in fish. Transcriptomic analysis unveiled 17 genes consistently observed in both NAFLD and insulin resistance (IR), along with an additional 28 genes identified in both the adipocytokine signaling pathway and IR. These shared genes were also found within the NAFLD dataset, suggesting that hepatic IR may play a prominent role in the development of PFHxS-induced NAFLD. In conclusion, our study suggests that environmental exposure to PFHxS could be a potential risk factor for the development of NAFLD, challenging the earlier notion of PFHxS being safer as previously claimed.

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“…Previous work by our group and the group of Yamada et al 21,22 , showed that mice with heterozygous mutation of Sf3b4 did not model craniofacial malformations seen in patients, but had growth retardation, microcephaly, as well as homeotic posteriorization of the axial skeleton. Furthermore, although craniofacial and eye abnormalities found in SF3B4 - related patients have been phenocopied in zebrafish and Xenopus embryos with knock down of Sf3b4 23,24 , vertebrae and heart defects were not found. Additionally, though RNAseq analysis showed few changes in gene expression, a significant number of genes including histone modifiers that regulate Hox expression, were abnormally spliced in heterozygous mouse embryos and somites 21 .…”

Section: Introductionmentioning

confidence: 99%

Etiology of Craniofacial and Cardiac Malformations in a Mouse Model of SF3B4-Related Syndromes

Kumar,

Bareke,

Lee

et al. 2024

Preprint

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Pathogenic variants in SF3B4 are responsible for the acrofacial disorders Nager and Rodriguez Syndrome, also known as SF3B4-related Syndromes, associated with malformations in the head, face, limbs, vertebrae as well as the heart. To uncover the etiology of craniofacial malformations found in SF3B4-related syndromes, mutant mouse lines with homozygous deletion of Sf3b4 in neural crest cells (NCC) were generated. Like in human patients, these embryos had craniofacial and cardiac malformations with variable expressivity and penetrance. The severity and survival of Sf3b4 NCC mutants was modified by the level of Sf3b4 in neighbouring non NCC. RNA sequencing analysis of heads of embryos prior to morphological abnormalities showed significant changes in expression of genes forming the NCC regulatory network, as well as an increase in exon skipping. We identified several key transcription factors and histone modifiers involved in craniofacial and cardiac development with increased exon skipping. Increased exon skipping was also associated with use of a more proximal branch point, as well as an enrichment in thymidine bases in the 50bp around the branch points. We propose that decrease in Sf3b4 causes changes in the expression and splicing of transcripts required for proper craniofacial and cardiac development, leading to abnormalities.

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Dysregulation of Spliceosomes Complex Induces Retinitis Pigmentosa–Like Characteristics in sf3b4-Depleted Zebrafish

Cited by 11 publications

References 52 publications

Human stem cell model of neural crest cell differentiation reveals a requirement of SF3B4 in survival, maintenance, and differentiation

Human stem cell model of neural crest cell differentiation reveals a requirement of SF3B4 in survival, maintenance, and differentiation

PFHxS Exposure and the Risk of Non-Alcoholic Fatty Liver Disease

Etiology of Craniofacial and Cardiac Malformations in a Mouse Model of SF3B4-Related Syndromes

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