A Mutation in the Mouse Gene Leads to Impaired Hedgehog Signaling

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The Hedgehog (Hh) signaling pathway determines pattern formation in many developing tissues, e.g., during digit formation in the limbs, by regulating proteins of the Gli family. Activation of these proteins requires their transport to the tip of the primary cilium (an antenna-like sensory structure of the cell), and subsequent dissociation from their negative regulator, Sufu. Little is known about the mechanism underlying this dissociation. To gain new insights into Hh signaling, we analyzed the mutant mouse hop-sterile (hop), whose developmental defects suggest that the primary cilia are dysfunctional. We discovered that the hop mutation lies in the Ttc26 gene, and that levels of the encoded protein are low in hop mice. Normal Ttc26 was found to bind to Intraflagellar Transport (IFT) complex B, a structure essential for building the cilium and moving proteins towards its tip. Nevertheless, unlike previously characterized mutations that affect IFT complex B, hop did not interfere with either the formation of primary cilia or the accumulation of Gli at their tips, but rather with dissociation of Gli from Sufu. Our results provide novel insights into Hh signaling, demonstrating that efficient coupling between Gli's accumulation at the ciliary tip and its dissociation from Sufu depends on Ttc26.

Vyšlo v časopise: A Mutation in the Mouse Gene Leads to Impaired Hedgehog Signaling. PLoS Genet 10(10): e32767. doi:10.1371/journal.pgen.1004689
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004689

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