The primary cilium is a solitary microtubule-based organelle that protrudes from the cell surface and is found on most vertebrate cells. Primary cilia originate in the mother centriole of the centrosome and are elongated and maintained by intraflagellar transport (IFT). Previous transmission electron microscopy (TEM) studies defined two different ciliogenesis pathways for primary cilia. In epithelial cells, the mother centriole appears to dock directly at the apical plasma membrane; from there, the axoneme grows out toward the extracellular environment. This is called the extracellular pathway. In contrast, in fibroblasts and smooth muscle cells, the cilium appears to first grow within the cell body, upon docking of the mother centriole to a Golgi-derived primary ciliary vesicle. The growth of the axoneme takes place within this vesicle. Fusion of this vesicle with the plasma membrane finally allows the cilium to access the extracellular environment. This is called the intracellular pathway. Thus far, nothing is known about how these two pathways are differentially regulated at the molecular levels. Ciliary dysfunction disrupts Hedgehog (Hh) signaling by affecting the activity of the Gli2 and Gli3 transcription factors, two primary regulators of Hh signaling. Most known ciliary gene mutations identified thus far result in failed Gli2 activation and decreased Gli3 repressor levels, but the underlying molecular mechanisms remain poorly understood. We recently mutated the mouse Dzip1L gene, which encodes a centriolar protein. Dzip1L mutant mice exhibit polydactyly and an enlarged forebrain and midbrain. Loss of Dzip1L results in reduced Gli3 repressor activity but does not affect Gli2 activation. Surprisingly, although cilia ae normal in neuroepithelial cells of the Dzip1L mutant brain, there is a pronounced paucity of cilia in mutant limb bud mesenchymal cells and embryonic fibroblasts. Thus, Dzip1L is the first known cilia-related protein that specifically regulates ciliogenesis in fibroblasts, but not epitheial cells, and affects only Gli3 processing but not Gli2 activation. Our objective is to understand how Dzip1L mutation affects Gli3 processing but not Gli2 activation and how Dzip1L differentially regulates the two ciliogenesis pathways using genetic, molecular, and cell biological approaches.
The primary cilium is an antenna-like structure that protrudes from the cell surface. It functions as a sensory organelle and as a signaling center for many signaling molecules such as Hedgehog. Defects in primary ciliary formation and function are associated with a variety of diseases in humans. Thus, understanding how cilia are built and how failed cilia formation affects Hedgehog signaling will provide insight into the identification f potential therapeutic targets, possibly leading to the development of drugs for cilia- and Hedgehog-related human diseases.
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