NIH Research Festival
Centrioles make up the core of centrosomes which function as microtubule-organizing centers of the cell. Centrioles perform two distinct cellular functions: (i) they form core components required to build the centrosome and (ii) they form the basal body that templates formation of the cilium, a microtubule-based specialized signaling organelle. CENPJ is a central component of centrioles required for centriole duplication. Mutations in CENPJ cause Seckel syndrome and primary microcephaly, leading to facial defects including hypoplasia of the lower jaw (micrognathia), facial midline abnormalities, premature closure of cranial sutures (craniosynostosis), and tooth abnormalities. Understanding how centriole loss affects facial development is critical for developing novel therapeutic interventions.
To investigate the role of centrioles in craniofacial development, we conditionally deleted CenpJ in craniofacial tissues of mouse embryos using the Sox9-cre driver. The resulting mice displayed underdeveloped jaws, midline facial defects, and skull abnormalities similar to Seckel syndrome patients. Defects appeared at embryonic day 10.5 (E10.5), starting with a smaller jaw and widened midface. By E11.5-12.5, midline facial clefting occurred. Increased cell death in the mandibular arch and p53 activation were observed.
Remarkably, deleting p53 fully rescued the craniofacial phenotypes in CenpJ-deficient mice, emphasizing p53's role in facial dysmorphology due to centriole loss. This discovery sheds light on the pathways involved in facial development and highlights p53 as a potential target for therapeutic interventions.
Scientific Focus Area: ACI/IRS
This page was last updated on Monday, September 25, 2023