Mouse models of human craniofacials spliceosomopathies: Are they neurocristopathies?
Bibliographic record
Abstract
Splicing, the removal of introns from pre‐messenger RNA is an essential step for expression of most genes in multicellular organisms and for expanding the number of proteins coded by genomes. Recently, exome sequencing revealed that mutations in splicing factors and small nuclear ribonucleoprotein particles (snRNPs) which form core components of the spliceosome, are responsible for craniofacial malformations. Our group used in situ hybridization to examine expression of three core components of the spliceosome: Eftud2 – mutated in patients with mandibulofacial dysostosis, Guion‐Almeida type (MFDGA); SnrpB – responsible for Cerebrocostomandibular Syndrome (CMS); and Sf3b4 which is responsible for Nager syndrome. Herein, we report expression of Eftud2, Sf3b4 and SnrpB during craniofacial development. In addition, we used CRISPR/Cas9 to generate mice with deletion ( Eftud2 del) and conditional mutation of exon 2 of Eftud2 (Eftud2 flox) . At embryonic days (E) 7.5 and 8.5, Eftud2 was highly expressed in ectodermal and mesodermal components of the future craniofacial region, by E9.5 expression was also found in the body wall and developing heart. Eftud2 del heterozygous mice were viable and fertile, though these embryos showed reduced levels of Eftud2 mRNA and protein. In contrast, Eftud2 del homozygous mutant embryos arrest at E3.5 and failed to grow and hatch ex vivo . To examine the requirement for Eftud2 in neural crest cells, the Wnt1‐Cre2 transgenic line was used to delete exon 2 of Eftud2 specifically in that lineage. Eftud2 flox homozygous mutant embryos carrying the Wnt1‐Cre2 transgene displayed hypoplasia of the midbrain and pharyngeal arches starting at E9.5. By E11.5, most embryos also had an open neural tube and all embryos showed exencephaly at E14.5. Cartilage preparations revealed an absence of cartilage in the head, reduction/or absence of Meckel's cartilage, and abnormal inner ear development. Since deletion of exon 2 is predicted to generate a truncated protein with partial function, our data suggest that normal levels of Eftud2 is crucial in neural crest cells for normal craniofacial development. Future studies are focused on elucidating the molecular and transcriptional basis of MFDM using this mouse model. Support or Funding Information Canadian Institute of Health Research (MOP#142452) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.006 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".