Published Nov. 1, 2016
PLOS Genetics

When primary cilia do not function properly during development, one of the most severe outcomes can be disfiguring mid-facial widening in utero. Now scientists have a deeper understanding of the molecular mechanisms that drive ciliopathies.

A research team led by Samantha Brugmann, PhD, of the divisions of Plastic Surgery and Developmental Biology, demonstrated that ciliopathic facial phenotypes are generated by the loss of functional transcription factors GLI2 and GLI3, and that the pathology is caused by a derepression mechanism.

GLI proteins are transcriptional effectors of the Hedgehog pathway, which helps determine the fate of cells during embryonic development. Several previous studies have suggested that mid-facial development relies heavily on the repressive function of the GLI3 protein. However, loss of that protein alone did not reproduce the ciliopathic phenotype. It took the combined loss of GLI2 and GLI3 to do that.

“It was particularly surprising that this other member of the GLI family, GLI2 was playing a role in mid-facial patterning,” Brugmann says. “Previously only GLI3 had been implicated.”

The team also showed that the loss of intraflagellar transport proteins (KIF3a or IFT88) caused aberrant GLI processing. That prompted an increase in GLI3FL and GLI2FL.

Novel approaches by first-author Ching-Fang Chang, PhD, were critical to the study’s success, Brugmann says.

“This was only possible because she has a tremendous technical skill set,” Brugmann says. “She was willing to do very challenging experiments never before done on the tissues that make up the midface.”