Grant: Project Grant

The primary cilium is an important chemical and mechanical antenna of practically every cell in the body. This organelle, once thought to be vestigial, is a major organizer of differentiation, cell growth and proliferation. The paramount importance of the cilium became obvious with the recognition that errors in the genes that encode cilium proteins cause serious and ultimately often lethal hereditary diseases, so called ciliopathies. The most common of these is polycystic kidney disease, but mutation in ciliary proteins lead to a set of other syndromes too, with wide-ranging symptoms including impaired mental function due to malformation of the nervous system, blindness, left-right side inversion, bone deformities, obesity as well as liver, heart and other kidney diseases. Moreover, acquired (non-inherited) abnormalities in the cilium contribute to cancer and chronic scarring of tissues (fibrosis). While complex machineries control both the assembly and the disassembly of the cilium and coordinate these evens with cell division, the underlying molecular mechanisms are not well understood. Our proposal stems from our discovery that two proteins, myocardin-related transcription factor (MRTF) and serum response factor (SRF) regulate cilium assembly and disassembly. These factors, controlled by the cell's skeleton, can drive genes, some of which are necessary for cilium maintenance. However, in addition to their gene-regulating (transcriptional) effect, we found that MRTF and SRF are also part of the cilium itself. These recognitions open a new way to affect the cilium. Using a variety of cell and molecular biology techniques, we propose to uncover how these proteins contribute to the normal structure and function of the primary cilium, and how they might be involved in serious ciliopathies and cancer-related cilium defects. Understanding these processes will lead to fundamental insights necessary for correcting cilium errors.