The Hedgehog signaling pathway is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathway also has roles in the adult. Diseases associated with the malfunction of this pathway include cancer. The Hedgehog signaling pathway is one of the key regulators of animal development and is present in all bilaterians. The pathway takes its name from its polypeptide ligand, an intracellular signaling molecule called Hedgehog (Hh) found in fruit flies of the genus Drosophila; fruit fly larvae lacking the Hh gene are said to resemble hedgehogs. Hh is one of Drosophila's segment polarity gene products, involved in establishing the basis of the fly body plan. The molecule remains important during later stages of embryogenesis and metamorphosis. Mammals have three Hedgehog homologues, Desert (DHH), Indian (IHH), and Sonic (SHH), of which Sonic is the best studied. The pathway is equally important during vertebrate embryonic development and is therefore of interest in evolutionary developmental biology. In knockout mice lacking components of the pathway, the brain, skeleton, musculature, gastrointestinal tract and lungs fail to develop correctly. Recent studies point to the role of Hedgehog signaling in regulating adult stem cells involved in maintenance and regeneration of adult tissues. The pathway has also been implicated in the development of some cancers. Drugs that specifically target Hedgehog signaling to fight this disease are being actively developed by a number of pharmaceutical companies.
Discovery
In the 1970s, a fundamental problem in developmental biology was to understand how a relatively simple egg can give rise to a complex segmented body plan. In the late 1970s Christiane Nüsslein-Volhard and Eric Wieschaus isolated mutations in genes that control development of the segmented anterior-posterior body axis of the fly; their "saturation mutagenesis" technique resulted in the discovery of a group of genes involved in the development of body segmentation, helping to found the field of evolutionary developmental biology. In 1995, they shared the Nobel Prize with Edward B. Lewis for their work studying genetic mutations in Drosophila embryogenesis. The Drosophila hedgehog (hh) gene was identified as one of several genes important for creating the differences between the anterior and posterior parts of individual body segments. The fly hh gene was independently cloned in 1992 by the labs of Jym Mohler, Philip Beachy, Thomas B. Kornberg and Saigo Kaoru. Some hedgehog mutants result in abnormally-shaped embryos that are unusually short and stubby compared to wild type embryos. The function of the hedgehog segment polarity gene has been studied for influence on the normally polarized distribution of larval cuticular denticles as well as features on adult appendages such as legs and antennae. Rather than the normal pattern of denticles, hedgehog mutant larvae tend to have "solid lawns" of denticles (Figure 1). The appearance of the stubby and "hairy" larvae inspired the name 'hedgehog'.
Fruit fly
Mechanism Insect cells express a full size zinc-finger transcription factor Cubitus interruptus (Ci), which forms a complex with the kinesin-like protein Costal-2 (Cos2) and is localized in the cytoplasm bound to cellular microtubules (Figure 2). The SCF complex targets the 155 kDa full length Ci protein for proteosome-dependent cleavage, which generates a 75 kDa fragment (CiR). CiR builds up in the cell and diffuses into the nucleus, where it acts as a co-repressor for Hedgehog (Hh) target genes. The steps leading to Ci protein proteolysis include phosphorylation of Ci protein by several protein kinases; PKA, GSK3β and CK1 (Figure 2). The Drosophila protein Slimb is part of an SCF complex that targets proteins for ubiquitylation. Slimb binds to phosphorylated Ci protein. In the absence of Hh (Figure 3), a cell-surface transmembrane protein called Patched (PTCH) acts to prevent high expression and activity of a 7 membrane spanning receptor called Smoothened (SMO). Patched has sequence similarity to known membrane transport proteins. When extracellular Hh is present (Figure 3), it binds to and inhibits Patched, allowing Smoothened to accumulate and inhibit the proteolytic cleavage of the Ci protein. This process most likely involves the direct interaction of Smoothened and Costal-2 and may involve sequestration of the Ci protein-containing complex to a microdomain where the steps leading to Ci protein proteolysis are disrupted. The mechanism by which Hh binding to Patched leads to increased levels of Smoothened is not clear (Step 1 in Figure 3). Following binding of Hh to Patched, Smoothened levels increase greatly over the level maintained in cells when Patched is not bound to Hh. It has been suggested that phosphorylation of Smoothened plays a role in Hh-dependent regulation of Smoothened levels. In cells with Hh-activated Patched (Figure 3), the intact Ci protein accumulates in the cell cytoplasm and levels of CiR decrease, allowing transcription of some genes such as decapentaplegic (dpp, a member of the BMP growth factor family). For other Hh-regulated genes, expression requires not only the loss of CiR but also the positive action of uncleaved Ci to act as a transcriptional activator. Costal-2 is normally important for holding Ci protein in the cytoplasm, but interaction of Smoothened with Costal-2 allows some intact Ci protein to go to the nucleus. The Drosophila protein Fused (Fu in Figure 3) is a protein kinase that binds to Costal-2. Fused can inhibit Suppressor of Fused (SUFU), which in turn interacts with Ci to regulate gene transcription in some cell types.
Role
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