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Cilia in development and regeneration

Over the past fifteen years, a role for cilia in nearly all cells and tissues and in many key developmental processes has emerged. The remarkably pleiotropic effects of mutation in cilia genes (mental retardation, anosmia, obesity, cystic kidney disease, blindness) reflect the ubiquity of cilia as an essential organelle.

We discovered that cilia control the embryonic fluid flow that drives the generation of left-right organ asymmetry, nephron filtration, and cerebrospinal fluid movement. Using forward genetics we positionally cloned zebrafish mutants from the MGH large-scale screen and identified a novel intraflagellar transport protein, fleer/ift70 that regulates tubulin post-translational modifications.

We characterized all tubulin-modifying enzymes in zebrafish and demonstrated that tubulin glutamylation and glycylation both play critical roles in cilia stability and function.

Beyond development, cilia and transcriptional regulation of ciliogenesis is associated with responses of tissues to injury and mechanical forces. We discovered that master regulators of ciliogenesis, foxj1a and rfx2, are rapidly induced in kidney cells by mechanical stretch. This work highlights the dynamic nature of ciliogenesis and discovered a potentially important role for cilia in kidney tubule lumen maintenance, for instance in cystic kidney disease. It also suggests new roles of cilia in epithelial regeneration. Recently we identified a regulatory defect in a new zebrafish cystic kidney ENU mutant of the lrrc50 cilia motility/dynein assembly gene. Identification of the responsible enhancer mutation could reveal novel aspects of cilia gene regulation.