Spliceosomopathies and neurocristopathies: Two sides of the same coin?

Beauchamp, Marie‐Claude; Alam, Sabrina; Kumar, Shruti; Jerome-Majewska, Loydie A.

doi:10.1002/dvdy.183

Cited by 46 publications

(54 citation statements)

References 136 publications

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“…It has become clear that alternative splicing in different tissues is regulated by coordinated networks of splicing regulators (Ule and Blencowe, 2019). The importance of alternative splicing in craniofacial development is demonstrated by the observation that abnormalities in spliceosome or splicing regulators occur in several human birth defects often involving the craniofacial complex (Bain et al, 2016;Marques et al, 2016;Loiselle and Sutherland, 2018;Berube-Simard and Pilon, 2019;Beauchamp et al, 2020;Griffin and Saint-Jeannet, 2020). Two splicing regulators involved in promoting differential splicing in the ectoderm -Esrp1/2 -are known to cause mouse orofacial clefting of the lip and palate when deleted (Warzecha et al, 2009;Bebee et al, 2015;Lee et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

An Alternative Splicing Program for Mouse Craniofacial Development

et al. 2020

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Alternative splicing acts as a fundamental mechanism to increase the number of functional transcripts that can be derived from the genome-and its appropriate regulation is required to direct normal development, differentiation, and physiology, in many species. Recent studies have highlighted that mutation of splicing factors, resulting in the disruption of alternative splicing, can have profound consequences for mammalian craniofacial development. However, there has been no systematic analysis of the dynamics of differential splicing during the critical period of face formation with respect to age, tissue layer, or prominence. Here we used deep RNA sequencing to profile transcripts expressed in the developing mouse face for both ectodermal and mesenchymal tissues from the three facial prominences at critical ages for facial development, embryonic days 10.5, 11.5, and 12.5. We also derived separate expression data from the nasal pit relating to the differentiation of the olfactory epithelium for a total of 60 independent datasets. Analysis of these datasets reveals the differential expression of multiple genes, but we find a similar number of genes are regulated only via differential splicing, indicating that alternative splicing is a major source of transcript diversity during facial development. Notably, splicing changes between tissue layers and over time are more prevalent than between prominences, with exon skipping the most common event. We next examined how the variation in splicing correlated with the expression of RNA binding proteins across the various datasets. Further, we assessed how binding sites for splicing regulatory molecules mapped with respect to intron exon boundaries. Overall these studies help define an alternative splicing regulatory program that has important consequences for facial development.

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Section: Introductionmentioning

confidence: 99%

An Alternative Splicing Program for Mouse Craniofacial Development

et al. 2020

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“…Patients with MFDM exhibit a variety of clinical findings and the most common are craniofacial defects such as microcephaly, developmental delay, mandibular and malar hypoplasia as well as external ear anomalies. In addition, as no correlation is found between patient`s genotypes and their clinical characteristics, these mutations are predicted to be loss-of-function mutations and suggest that the developing craniofacial region is more sensitive to reduced levels of EFTUD2 when compared to other embryonic cell types (reviewed in (Beauchamp et al, 2020)). Here, we report that altered splicing caused by the loss of Eftud2 results in the reduced inclusion of exon 3 of Mdm2 and nuclear accumulation of P53 in the neural crest cells.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, homozygous Eftud2 (Eftud2 -/-) mutant blastocysts failed to implant, precluding analysis of the role of Eftud2 during craniofacial development. These and other past studies confirmed that Eftud2 is an essential gene, but its role in neural crest cells, the precursors of bones and cartilages affected in the head and face of MFDM patients, has not been examined (Beauchamp et al, 2020;Deml et al, 2015;Lei et al, 2017;Wu et al, 2019). Therefore, we have generated a conditional Eftud2 knock-out mouse (Eftud2 loxP/+ ) in which exon 2 is flanked by loxP sequences to study the role of Eftud2 during craniofacial development.…”

Section: Introductionmentioning

confidence: 86%

“…The sequential steps in splicing include recognition of a 5'-splice site via the U1/U11 snRNP, binding of U2/U12 snRNP to the branch site on the intron, recruitment of the preassembled U4/U6.U5 or U4atac/U6atac/U5 snRNPs, cleavage of the intervening intron, and ligation of the two exons. This process is ubiquitous and yet, mutations in components of the spliceosome can result in tissue-specific abnormalities ranging from retinitis pigmentosa to craniofacial malformations (Beauchamp et al, 2020;Daguenet et al, 2015;Griffin and Saint-Jeannet, 2020;Lehalle et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Mis-splicing ofMdm2leads to Increased P53-Activity and Craniofacial Defects in a MFDMEftud2Mutant Mouse Model

Beauchamp¹,

Djedid

Bareke

et al. 2020

Preprint

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EFTUD2, a GTPase and core component of the splicesome, is mutated in patients with mandibulofacial dysostosis with microcephaly (MFDM). We generated a mutant mouse line with conditional mutation in Eftud2 and used Wnt1-Cre2 to delete it in neural crest cells. Homozygous deletion of Eftud2 leads to neural crest cell death and malformations in the brain and craniofacial region of embryos. RNAseq analysis of embryonic mutant heads revealed a significant increase in exon skipping, in retained introns and enriched levels of Mdm2 transcripts lacking exon 3. Mutants also had increased nuclear P53, higher expression of P53-target genes, and increased cell death. Their craniofacial development was significantly improved when treated with Pifithrin-α, an inihibitor of P53. We propose that craniofacial defects caused by mutations of EFTUD2 are a result of mis-splicing of Mdm2 and P53-associated cell death. Hence, drugs that reduce P53 activity may help prevent craniofacial defects associated with spliceosomopathies.

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“…BMKS is one of five developmental craniofacial disorders caused by variants in core spliceosome components [6,17]. Given the universality of pre-mRNA splicing in the processing of all human pre-mRNAs, the very specific and tissue-restricted craniofacial phenotypes of these disorders are remarkable.…”

Section: Introductionmentioning

confidence: 99%

Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells

et al. 2020

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The craniofacial developmental disorder Burn-McKeown Syndrome (BMKS) is caused by biallelic variants in the pre-messenger RNA splicing factor gene TXNL4A/DIB1. The majority of affected individuals with BMKS have a 34 base pair deletion in the promoter region of one allele of TXNL4A combined with a loss-of-function variant on the other allele, resulting in reduced TXNL4A expression. However, it is unclear how reduced expression of this ubiquitously expressed spliceosome protein results in craniofacial defects during development. Here we reprogrammed peripheral mononuclear blood cells from a BMKS patient and her unaffected mother into induced pluripotent stem cells (iPSCs) and differentiated the iPSCs into induced neural crest cells (iNCCs), the key cell type required for correct craniofacial development. BMKS patient-derived iPSCs proliferated more slowly than both mother-and unrelated control-derived iPSCs, and RNA-Seq analysis revealed significant differences in gene expression and alternative splicing. Patient iPSCs displayed defective differentiation into iNCCs compared to maternal and unrelated control iPSCs, in particular a delay in undergoing an epithelial-to-mesenchymal transition (EMT). RNA-Seq analysis of differentiated iNCCs revealed widespread gene expression changes and mis-splicing in genes relevant to craniofacial and embryonic development that highlight a dampened response to WNT signalling, the key pathway activated during iNCC differentiation. Furthermore, we identified the mis-splicing of TCF7L2 exon 4, a key gene in the WNT pathway, as a potential cause of the downregulated WNT response in patient cells. Additionally, mis-spliced genes shared common sequence properties such as length, branch point to 3' splice site (BPS-3'SS) distance and splice site strengths, suggesting that splicing of particular subsets of genes is particularly sensitive to changes in TXNL4A expression. Together, these data provide the first

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Spliceosomopathies and neurocristopathies: Two sides of the same coin?

Cited by 46 publications

References 136 publications

An Alternative Splicing Program for Mouse Craniofacial Development

An Alternative Splicing Program for Mouse Craniofacial Development

Mis-splicing ofMdm2leads to Increased P53-Activity and Craniofacial Defects in a MFDMEftud2Mutant Mouse Model

Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells

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