hedgehog regulation in genetic disorders

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Research from Development. Apr 28 2004

The zebrafish iguana locus encodes Dzip1, a novel zinc-finger protein

required for proper regulation of Hedgehog signaling.

Sekimizu K, Nishioka N, Sasaki H, Takeda H, Karlstrom RO, Kawakami A.

Members of the Hedgehog (Hh) family of intercellular signaling molecules

play crucial roles in animal development. Aberrant regulation of Hh

signaling in humans causes developmental defects, and leads to various

genetic disorders and cancers. We have characterized a novel regulator

of Hh signaling through the analysis of the zebrafish midline mutant

iguana (igu). Mutations in igu lead to reduced expression of Hh target

genes in the ventral neural tube, similar to the phenotype seen in

zebrafish mutants known to affect Hh signaling. Contradictory at first

sight, igu mutations lead to expanded Hh target gene expression in

somites. Genetic and pharmacological analyses revealed that the

expression of Hh target genes in igu mutants requires Gli activator

function but does not depend on Smoothened function. Our results show

that the ability of Gli proteins to activate Hh target gene expression

in response to Hh signals is generally reduced in igu mutants both in

the neural tube and in somites. Although this reduced Hh signaling

activity leads to a loss of Hh target gene expression in the neural

tube, the same low levels of Hh signaling appear to be sufficient to

activate Hh target genes throughout somites because of different

threshold responses to Hh signals. We also show that Hh target gene

expression in igu mutants is resistant to increased protein kinase A

activity that normally represses Hh signaling. Together, our data

indicate that igu mutations impair both the full activation of Gli

proteins in response to Hh signals, and the negative regulation of Hh

signaling in tissues more distant from the source of Hh. Positional

cloning revealed that the igu locus encodes Dzip1, a novel intracellular

protein that contains a single zinc-finger protein-protein interaction

domain. Overexpression of Igu/Dzip1 proteins suggested that Igu/Dzip1

functions in a permissive way in the Hh signaling pathway. Taken

together, our studies show that Igu/Dzip1 functions as a permissive

factor that is required for the proper regulation of Hh target genes in

response to Hh signals.