Searching for Creative Ways to Prevent Treacher Collins Syndrome

Children who are born with the rare craniofacial defect Treacher Collins syndrome (TCS) often have facial deformities and other physical defects related to the disorder.

These children often undergo multiple surgeries in an attempt to repair the physical defects caused by TCS. Improved scientific understanding of how TCS begins at the most basic level—in the neural crest cells (NCCs) that give rise to the cartilage, bone and connective tissue of the head and face—is critical.

Investigator Paul Trainor, PhD, has been dedicated to generating that knowledge. He and his team have used mouse models to define how the loss-of-function mutation in the gene Tcof1 disrupts NCCs to cause TCS. Until recently, Tcof1 was the only gene known to play a role in TCS, but a recent study implicated polr1c and polr1d as causative genes in the craniofacial development disorder.

A developing zebrafish that harbors a genetic mutation implicated in Treacher Collins syndrome has a reduced number of neural crest cells (green). Some precursors of the neural crest cell population are undergoing cell death (red).

“Using zebrafish as our animal model, we set out to explore the functional roles of polr1c and polr1d during embryogenesis and more specifically in craniofacial development,” explains Kristin Watt, PhD, postdoctoral scientist in the Trainor Lab. Watt is lead author of the resulting research paper, which reports that loss-of-function mutations in polr1c and polr1d functioned similarly to the Tcof1 mutation in disrupting a crucial component (ribosome biogenesis) of NCCs. The disruption of ribosome biogenesis issues a distress call that compels the p53 cell death gene to kill NCCs. With the death of NCCs, the body no longer has sufficient numbers of cells to construct the craniofacial skeleton.

The Trainor Lab also determined that TCS, at least in the animal model, is reversible by experimentally blocking the actions of the p53 gene. In doing so, the population of NCCs was restored to its normal level, and TCS did not occur.

These results were published in the July 22, 2016, issue of PLoS Genetics.