How do cells “count” internal structures? Our research seeks to tackle this question by identifying and decoding the circuitry that nature designed to keep track of centrioles. Centrioles are specialized organelles with a striking functional duality. First, they recruit a surrounding pericentriolar material (PCM) to form centrosomes, which organize the interphase microtubule cytoskeleton of most animal cells and form the poles of the mitotic spindle. Second, centrioles can be modified to form basal bodies, which template the formation of cilia and play central roles in cellular signaling, fluid movement, and locomotion. For centrioles to effectively control these diverse cellular processes, their biogenesis and number must be carefully controlled; aberrations in centriole number and structure have been implicated in the pathogenesis of several devastating diseases, including cancer and neurodevelopmental disorders. 

 

Our lab focuses on understanding the mechanisms controlling centriole homeostasis and how dysregulation of these processes contributes to human disease. We employ a range of approaches from biochemical characterizations of proteins to genome-wide CRISPR screens and analysis of genetically engineered mice. We have identified mechanisms contributing to centriole assembly, studied the requirement of centrioles for proliferation in mammalian cells, and examined how alterations in centriole number contribute to cancer and neurodevelopmental disorders. A long-term goal of our lab is to exploit our foundational discoveries to improve human health. 

Research Interests

Centrioles are microtubule-based structures that recruit a surrounding pericentriolar material to form the centrosome. Centrosomes nucleate the assembly of the microtubule cytoskeleton in interphase cells and form the poles of the mitotic spindle during cell division. Centriole duplication occurs once per cell cycle and is controlled by the conserved master regulator Polo-like kinase 4 (PLK4). Abnormal expression of PLK4 has been linked with tumorigenesis and drugs targeting PLK4 have recently entered clinical trials. Although significant progress has been made in understanding centriole...

Specialized multiciliated cells (MCCs) elaborate dense motile cilia that beat in a coordinated manner to drive fluid flow over epithelial surfaces. Defects in motile cilia formation or beating lead to fluid buildup in the brain, increased respiratory tract infections, and infertility. Centrioles reside at the base of each cilium and serve as a template for cilium assembly. In cycling cells, centriole formation is tightly controlled so that a single new procentriole forms adjacent to each of the two parent centrioles. However, MCCs deviate from this strict numerical control to produce...

Mitotic cells are susceptible to genomic alterations through the breakage or mis-segregation of chromosomes. Cells reduce the risk of these defects by carefully monitoring DNA integrity and chromosome attachments with quality-control checkpoints. Our recent identification of a signaling pathway that prevents proliferation following centrosome loss raised the question of how this pathway operates to preserve the integrity of mitosis. To address this question, we designed and executed a pooled genome-wide CRISPR-Cas9 screen to discover essential regulators of the cell cycle arrest caused by...

The centrosome is the cell’s major microtubule-organizing center and plays an important role in mitosis, where it organizes the poles of the microtubule spindle apparatus that segregates the chromosomes. To maintain the fidelity of cell division, centrosome number must be strictly controlled. Cells begin the cycle with a single centrosome that duplicates only once to ensure cells have two copies of this organelle when they divide. This faithful control of centrosome number is deregulated in a wide array of tumor types, resulting in the acquisition of extra copies of centrosomes (referred...