Genetic dissection of Treacher Collins Syndrome: Polr1c and Polr1d

Abstract

Treacher Collins Syndrome (TCS) is a congenital disorder characterized by craniofacial deformities including external and middle ear defects, cleft palate and hypoplasia of facial bones. TCOF1 underlies TCS in humans and a mouse model was generated to investigate its developmental causes. Tcof1+/− mice show phenotypes similar to human TCS caused by a decrease in cranial neural crest cells (CNCC) that give rise to the majority of bone in the head and face. Tcof1 encodes the nucleolar phosphoprotein Treacle which functions in ribosomal DNA (rDNA) transcription. Tcof1+/− mice exhibit death of CNCC precursors due to a reduction in mature ribosomes. Recently, two more genes involved in rDNA transcription have been identified in TCS patients: POLR1C and POLR1D. To investigate the role of these genes in TCS we turned to zebrafish and mouse. Disruption of polr1c or polr1d in zebrafish results in specific craniofacial defects including loss of facial structures such as the ceratobranchials, hypoplasia of the cranial skeleton and deformed ethmoid plate. Similar to tcof mice, these defects arise from a reduction in CNCC caused by cell death. Further, neural crest specific knock out of Polr1c in mice leads to craniofacial defects similar to human TCS, including hypoplasia of the mandible and severe defects in the inner and middle ear bones. Our analysis suggests that both animal models can be used to dissect out the etiology of TCS.Grant Funding Source: AAA Postdoctoral Fellowship