No abstract

The Hedgehog (Hh) signaling pathway regulates development in animals ranging from flies to humans. Although its framework is conserved, differences in pathway components have been reported. A kinesin-like protein, Costal2 (Cos2), plays a central role in the Hh pathway in flies. Knockdown of a zebrafish homolog of Cos2, Kif7, results in ectopic Hh signaling, suggesting that Kif7 acts primarily as a negative regulator of Hh signal transduction. However, in vitro analysis of the function of mammalian Kif7 and the closely related Kif27 has led to the conclusion that neither protein has a role in Hh signaling. Using Kif7 knockout mice, we demonstrate that mouse Kif7, like its zebrafish and Drosophila homologs, plays a role in transducing the Hh signal. We show that Kif7 accumulates at the distal tip of the primary cilia in a Hh-dependent manner. We also demonstrate a requirement for Kif7 in the efficient localization of Gli3 to cilia in response to Hh and for the processing of Gli3 to its repressor form. These results suggest a role for Kif7 in coordinating Hh signal transduction at the tip of cilia and preventing Gli3 cleavage into a repressor form in the presence of Hh.

Ligand-dependent and ligand-independent activation of the Hedgehog (Hh) signaling pathway is involved in tumorigenesis. The importance of mutations in Hh pathway components leading to constitutive signaling has been well established in basal cell carcinoma and medulloblastoma. However, the role of ligand-driven Hh pathway activation in cancer remains to be established.

Genetic and cytologic data from Saccharomyces cerevisiae and mammals implicate the Mre11 complex, consisting of Mre11, Rad50, and Nbs1, as a sensor of DNA damage, and indicate that the complex influences the activity of ataxia-telangiectasia mutated (ATM) in the DNA damage response. Rad50 S/S mice exhibit precipitous apoptotic attrition of hematopoietic cells. We generated ATM-and Chk2-deficient Rad50 S/S mice and found that Rad50 S/S cellular attrition was strongly ATM and Chk2 dependent. The hypomorphic Mre11 ATLD1 and Nbs1 ⌬B alleles conferred similar rescue of Rad50 S/S -dependent hematopoietic failure. These data indicate that the Mre11 complex activates an ATM-Chk2-dependent apoptotic pathway. We find that apoptosis and cell cycle checkpoint activation are parallel outcomes of the Mre11 complex-ATM pathway. Conversely, the Rad50 S mutation mitigated several phenotypic features of ATM deficiency. We propose that the Rad50 S allele is hypermorphic for DNA damage signaling, and that the resulting constitutive low-level activation of the DNA damage response accounts for the partial suppression of ATM deficiency in Rad50 S/S Atm −/− mice.[Keywords: Checkpoints; DNA damage signaling; apoptosis]Supplemental material is available at http://www.genesdev.org.