AUTHOR=Cho Kah Yan , Kelley Brian P. , Monier Daisy , Lee Brendan , Szabo-Rogers Heather , Napierala Dobrawa 

TITLE=Trps1 Regulates Development of Craniofacial Skeleton and Is Required for the Initiation of Palatal Shelves Fusion

JOURNAL=Frontiers in Physiology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2019.00513

DOI=10.3389/fphys.2019.00513

ISSN=1664-042X

ABSTRACT=<p>Trichorhinophalangeal syndrome (TRPS) is an autosomal dominant disorder resulting from heterozygous mutations of the <italic>TRPS1</italic> gene. Common craniofacial abnormalities in TRPS patients include micrognathia, hypoplastic zygomatic arch, high-arched palate, and, occasionally, cleft palate. Studies have demonstrated that mice with a heterozygous <italic>Trps1</italic> mutation (<italic>Trps1<sup>+/−</sup></italic> mice) have similar features to patients with TRPS, including high-arched palates. However, mice with a homozygous <italic>Trps1</italic> mutation (<italic>Trps1<sup>−/−</sup></italic> mice) exhibit similar but more severe abnormalities, including cleft palate. Our study aimed to characterize the craniofacial phenotype to understand the role of <italic>Trps1</italic> in craniofacial development and gain insight on the cleft palate pathogenesis in <italic>Trps1</italic> deficiency. Whole-mount skeletal staining revealed hypoplastic skeletal and cartilaginous elements, steep nasal slope, and missing presphenoid in <italic>Trps1<sup>−/−</sup></italic> mice. Although several craniofacial skeleton elements were abnormal in <italic>Trps1<sup>−/−</sup></italic> mice, the <italic>Trps1</italic> deficiency did not appear to disrupt cranial vault development. All <italic>Trps1<sup>−/−</sup></italic> mice presented with cleft palate. Analyses of <italic>Trps1</italic> expression during palatogenesis detected Trps1 mRNA and protein in palatal mesenchyme and in specific regions of palatal epithelium, which suggested that Trps1 is involved in palatal fusion. <italic>Ex vivo</italic> culture experiments demonstrated that <italic>Trps1<sup>−/−</sup></italic> palatal shelves were unable to initiate the fusion process. On the molecular level, Trps1 deficiency resulted in decreased epithelial expression of proteins involved in palatal fusion, including chondroitin sulfate proteoglycan, transforming growth factor-beta 3, Twist1, and beta-catenin. Mesenchymal expression of chondroitin sulfate proteoglycan expression was unaffected, indicating a cell type-specific mechanism of <italic>Trps1</italic> regulation on chondroitin sulfate proteoglycan. In conclusion, we demonstrated that <italic>Trps1</italic> is involved in the development of craniofacial skeletal elements and in the initiation of the palatal shelves fusion. Furthermore, our studies uncovered that Trps1 is required for epithelial expression of several proteins involved in the palatal shelves fusion.</p>