Mutation in <i>Eftud2</i> causes craniofacial defects in mice via mis-splicing of <i>Mdm2</i> and increased P53

Beauchamp, Marie‐Claude; Djedid, Anissa; Bareke, Eric; Merkuri, Fjodor; Aber, Rachel; Tam, Annie; Lines, Matthew A.; Boycott, Kym M.; Stirling, Peter C.; Fish, Jennifer L.; Majewski, Jacek; Jerome-Majewska, Loydie A.

doi:10.1093/hmg/ddab051

Cited by 24 publications

(49 citation statements)

References 67 publications

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“…We postulate that SNRPB is required in all neural crest cells, and their derivatives, a fact that is supported by the reduced or absent aorticopulmonary septum that is found in the microCT scan of Snrpb ncc+/− mutants. Furthermore, we propose that aorticopulmonary septal defects contribute to death of Snrpb ncc+/− embryos, as was found in Eftud2 ncc/+ mutants (Beauchamp et al ., 2021). Finally, although phenotypes found in CCMS patients strongly suggested a requirement of SNRPB for endochondral ossification, our data clearly show abnormal development of bones formed via both endochondral and intramembranous ossification, indicating an early role for SNRPB in skeletal development.…”

Section: Discussionsupporting

confidence: 67%

“…We found increased skipping of exon 3 of Mdm2 and exon 7 of Mdm4, regulators of the P53 pathway in our RNA-Seq analysis and confirmed these increases by RT-PCR (Figure5). Increased skipping of these exons was previously reported in cultured Snrpb knockdown cells and shown to increase levels of nuclear P53 in mouse embryos with mutations in Eftud2 a core component of the spliceosome(Beauchamp et al, 2021, Alstyne et al, 2018, Correa et al, 2016. In fact, immunohistochemistry with an antibody to P53 revealed a significant enrichment of nuclear P53 in E9.5 mutant heads (Figure5G and 5H).…”

supporting

confidence: 67%

“…ncc/+ mutants(Beauchamp et al, 2021). Finally, although phenotypes found in CCMS patients strongly suggested a requirement of SNRPB for endochondral ossification, our data clearly show abnormal development of bones formed via both endochondral and intramembranous ossification, indicating an early role for SNRPB in skeletal development.In cell lines, knockdown of SNRPB decreased levels of the snRNAs that form the core of the U1, U4/U6, U5 and U6 snRNPs(Saltzman et al, 2011).…”

mentioning

confidence: 40%

“…In zebrafish and mouse, increased P53-activity contributes to craniofacial defects and knocking down or removing P53 genetically reduced apoptosis and improved development (Li L. et al ., 2017; Mao H. et al ., 2016). Additionally, we showed that the P53-inhibitor, Pifithrin-□, improved head and brain development in embryos with mutation of Eftud2 in the neural tube and neural crest (Beauchamp et al ., 2021). However, reducing or removing P53 genetically in the neural crest cells did not show complete rescue of craniofacial defects in Snrpb ncc+/− mutant embryos.…”

Section: Discussionmentioning

confidence: 99%

“…LiMao H. et al, 2016). Additionally, we showed that the P53-inhibitor, Pifithrin-, improved head and brain development in embryos with mutation of Eftud2 in the neural tube and neural crest(Beauchamp et al, 2021). However, reducing or removing P53 genetically in the neural crest cells did not show complete rescue of craniofacial defects in Snrpb ncc+/mutant embryos.…”

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confidence: 91%

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Snrpb, the CCMS gene, is required in neural crest cells for proper splicing of genes essential for craniofacial morphogenesis

Alam

Kumar

Beauchamp

et al. 2021

Preprint

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SummaryHeterozygous mutations in SNRPB, an essential core component of the five small ribonucleoprotein particles of the spliceosome, are responsible for Cerebrocostomandibular Syndrome (CCMS). However, the underlying pathophysiology of CCMS remains a mystery. We generated mouse embryos with heterozygous deletion of Snrpb and showed that they arrest shortly after implantation. We also showed that heterozygous deletion of Snrpb in the developing brain and neural crest cells models many of the craniofacial malformations found in CCMS, and results in death shortly after birth. Abnormalities in these mutant embryos ranged from cleft palate to a complete absence of the ventral portion of the face and are due to apoptosis of the neural crest cells in the frontonasal prominence and pharyngeal arches. RNAseq analysis of mutant embryonic heads prior to morphological defects revealed increased exon-skipping and intron-retention in association with increased 5’ splice strength. Mutant embryonic heads had increased exon-skipping in Mdm2 and Mdm4 negative regulators of the P53-pathway and a increased nuclear P53 and P53-target genes. However, removing one or both copies of P53 in Snrpb heterozygous mutant neural crest cells did not rescue craniofacial development. We also found a small but significant increase in exon-skipping of several transcripts required for head and midface development, including Smad2 and Rere. Furthermore, mutant embryos exhibited ectopic or missing expression of Fgf8 and Shh, which are required to coordinate face and brain development. Thus, we propose that mis-splicing of transcripts that regulate P53-activity and craniofacial-specific genes both contribute to craniofacial malformations.

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Section: Discussionsupporting

confidence: 67%

supporting

confidence: 67%

mentioning

confidence: 40%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 91%

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Snrpb, the CCMS gene, is required in neural crest cells for proper splicing of genes essential for craniofacial morphogenesis

Alam

Kumar

Beauchamp

et al. 2021

Preprint

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Spatiotemporal Investigation of Intercellular Heterogeneity via Multiple Photocaged Probes

Tsai

Chen

et al. 2023

Chemistry A European J

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Intercellular heterogeneity occurs widely under both normal physiological environments and abnormal disease‐causing conditions. Several attempts to couple spatiotemporal information to cell states in a microenvironment were performed to decipher the cause and effect of heterogeneity. Furthermore, spatiotemporal manipulation can be achieved with the use of photocaged/photoactivatable molecules. Here, we provide a platform to spatiotemporally analyze differential protein expression in neighboring cells by multiple photocaged probes coupled with homemade photomasks. We successfully established intercellular heterogeneity (photoactivable ROS trigger) and mapped the targets (directly ROS‐affected cells) and bystanders (surrounding cells), which were further characterized by total proteomic and cysteinomic analysis. Different protein profiles were shown between bystanders and target cells in both total proteome and cysteinome. Our strategy should expand the toolkit of spatiotemporal mapping for elucidating intercellular heterogeneity.

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Function of chromatin modifier Hmgn1 during neural crest and craniofacial development

Ihewulezi

Saint-Jeannet

2021

Genesis

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Summary The neural crest is a dynamic embryonic structure that plays a major role in the formation of the vertebrate craniofacial skeleton. Neural crest formation is regulated by a complex sequence of events directed by a network of transcription factors working in concert with chromatin modifiers. The high mobility group nucleosome binding protein 1 (Hmgn1) is a nonhistone chromatin architectural protein, associated with transcriptionally active chromatin. Here we report the expression and function of Hmgn1 during Xenopus neural crest and craniofacial development. Hmgn1 is broadly expressed at the gastrula and neurula stages, and is enriched in the head region at the tailbud stage, especially in the eyes and the pharyngeal arches. Hmgn1 knockdown affected the expression of several neural crest specifiers, including sox8, sox10, foxd3, and twist1, while other genes (sox9 and snai2) were only marginally affected. The specificity of this phenotype was confirmed by rescue, where injection of Hmgn1 mRNA was able to restore sox10 expression in morphant embryos. The reduction in neural crest gene expression at the neurula stage in Hmgn1 morphant embryos correlated with a decreased number of sox10‐ and twist1‐positive cells in the pharyngeal arches at the tailbud stage, and hypoplastic craniofacial cartilages at the tadpole stage. These results point to a novel role for Hmgn1 in the control of gene expression essential for neural crest and craniofacial development. Future work will investigate the precise mode of action of Hmgn1 in this context.

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Mutation in Eftud2 causes craniofacial defects in mice via mis-splicing of Mdm2 and increased P53

Cited by 24 publications

References 67 publications

Snrpb, the CCMS gene, is required in neural crest cells for proper splicing of genes essential for craniofacial morphogenesis

Snrpb, the CCMS gene, is required in neural crest cells for proper splicing of genes essential for craniofacial morphogenesis

Spatiotemporal Investigation of Intercellular Heterogeneity via Multiple Photocaged Probes

Function of chromatin modifier Hmgn1 during neural crest and craniofacial development

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