Cilia come in both motile and immotile forms. While motile cilia were known to have essential roles in the lung and respiratory system, primary cilia were widely considered vestigial structures. A significant paradigm shift in the field occurred with the generation of mouse mutants (such as the orpk mouse) that disrupt cilia formation. These new mouse mutants revealed important and novel roles for motile and immotile cilia and demonstrated that they are essential for mammalian development and tissue function. Defects in cilia have been implicated as the cause of a large and rapidly expanding group of human syndromes (Ciliopathies) with a wide range of developmental and disease phenotypes.
The objectives of my research program are to uncover mechanisms regulating assembly, maintenance, and functions of both motile and primary forms of cilia and to determine how defects in these processes contribute to developmental abnormalities and disease pathogenesis. To accomplish these goals, my group utilizes complementary cell, genetic, and biochemical approaches in mice, C. elegans, and cell culture to identify new proteins involved in ciliogenesis and cilia mediated signaling. Work from my group has identified novel components of the ciliary transition zone, an important domain controlling what protein enters or is retained in the cilium. We have provided critical insights into how the cilium regulates developmental pathways, such as hedgehog, and how alterations in cilia-mediated regulation of this pathway cause polydactyly, defects in endochondral bone formation, and abnormal skin and hair follicle morphogenesis. My group made fundamental contributions that connected ciliary dysfunction to the creation of cysts in the kidney, liver, and pancreas, and uncovered a new role for cilia on hypothalamic neurons in regulating satiation responses. We have shown that disruption of cilia on these neurons causes obesity and type II diabetes. We also identified genes important in regulating ciliary motility and waveform and determined that their loss in mice leads to hydrocephalus, bronchiectasis, and randomization of the left-right body axis. Importantly, as part of this work, we discovered that a mutation of one of these genes we identified in our mouse model is responsible for a form of primary ciliary dyskinesia (PCD) in humans. As in the mouse model, these human PCD patients frequently have left-right body situs defects.
In summary, the research conducted by my group is providing essential and innovative insights into how cilia are constructed and how they establish themselves as a unique signaling and sensory organelle with a distinct protein composition the rest of the cell membrane. We have uncovered many diverse and unexpected roles for cilia during development and in maintaining mammalian health.
