Deletion of Mouse <i>Sf3b4</i> in Neural Crest Cells Causes Craniofacial Abnormalities

The SF3B4 gene encodes a core component of the U2‐major spliceosome complex important during splicing of pre‐mRNA to mRNA. Recently, patients with two craniofacial disorders: Nager syndrome and Rodriguez syndrome were identified to carry rare mutations in this gene. The autosomal dominant nature of these syndromes indicates that this is due to haploinsufficiency for SF3B4 . Both disorders affect the face as well as the limb including both hands and feet. Nager syndrome patients survive and exhibit smaller jaw bones, smaller cheek bones, cleft palate, hearing problems as well as downward slanted eyelids. However, Rodriguez syndrome is much more severe, and patients often die before or soon after birth. We hypothesized that craniofacial abnormalities associated with reduced SF3B4 levels is due to tissue‐specific expression and requirement of this gene in neural crest cells. Using in situ hybridization, we showed that in mouse embryos, Sf3b4 was expressed ubiquitously from embryonic day (E)9.5 – E12.5. From E10.5 – E12.5, enriched expression of this gene was found in the maxillomandibular region, limb and tail bud. To generate a conditional mutant mouse line for Sf3b4 , we used CRISPR/Cas9 to insert LoxP sequences in intron 1 and 3 of this gene. To test our hypothesis, we mated Sf3b4 conditional mutant mice to Wnt1‐Cre2 transgenic mice to delete exons 2 and 3 specifically in neural crest cells. Heterozygous mutant embryos from these matings were normal. From E9.0 onwards, all homozygous mutant embryos had hypoplasia of the midbrain and pharyngeal arches. Homozygous mutant embryos died by E14.5. To examine neural crest cells and their derivatives in the head and craniofacial region, we used the Rosa26R lacZ reporter line. LacZ staining of mutant embryos showed a reduced number of neural crest cells in pharyngeal arches. Thus, our data suggests that craniofacial malformations due to mutations in SF3B4 are the result of reduced neural crest cells. Support or Funding Information Canadian Institutes of Health Research (CIHR)

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.