Hedgehog Signaling in Drosophila
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Hedgehog Signaling in Drosophila

The Hh (Hedgehog) proteins are evolutionarily conserved signaling molecules that control the normal growth and patterning of diverse animals including Drosophila and humans. In flies, Hh is required for multiple developmental processes such as embryonic segment patterning, eye and appendage development. A single Drosophila Hedgehog gene has three mammalian counterparts:SHh (Sonic Hedgehog),IHh (Indian Hedgehog), and DHh  (Desert Hedgehog). The Hh proteins are extracellular signaling molecules involved in embryonic patterning and organogenesis (Ref.1 & 2). In Drosophila, Hh activates the Smo  (Smoothened) G-protein-coupled receptor signal transduction pathway through its reaction with the Ptc (Patched) receptor. Activation of this pathway leads to activation of CI (Cubitus Interruptus) (the Drosophila homologue of Gli (Glioma-Associated Oncogene Homolog)), which in turn up regulates Ptc, leading to down regulation of CI. Hedgehog signaling triggers changes in responsive cells through a novel transduction mechanism that ultimately controls the transcription of specific target genes via the activity of zinc finger transcription factors of the CI/Gli family (Ref.3).

In flies, key Hedgehog signal transduction components includes the kinesin-related protein Cos2 (Costal-2), the serine/threonine kinase Fu  (Fused), and the PEST-containing protein SuFu (Suppressor of Fused). These proteins control CI cleavage, nucleo-cytoplasmic localization and activation. In fly embryos, Cos2, Fu, SuFu and CI  are associated in at least one cytoplasmic complex, which interacts with the microtubules in a Hedgehog-dependent manner (Ref.3). There is positive and negative feedback at the transcriptional level as the CI and Ptc genes are direct transcriptional targets of activation of the pathway. Ptc, a twelve-pass membrane protein binds Hh ligand, and in the absence of ligand, Ptc interacts with and inhibits Smo, a seven-pass membrane protein. This repression culminates in a transcription factor, CI75 in Drosophila and Gli in vertebrates acting as a transcriptional repressor. When Hh binds Ptc, its interactions with Smo  are altered such that Smo  is no longer inhibited. This leads to CI155 protein entering the nucleus (through G-Protein activation) and acting as a transcriptional activator for the same genes it represses when Ptc is free to interact with and inhibit Smo. The processing and nuclear import of CI  is regulated via a complex of CI with the cytoplasmic members of the Hh signaling pathway, Cos2, Fu  and SuFu. Cos2 tethers the CI-containing complex to the microtubules (Ref.2 & 4).

Upon Hh binding, the complex is released from microtubules and full-length CI  enters the nucleus. Kinases including GSK3H (Glycogen Synthase Kinase-3 Homolog), Slimb and PKA (Protein Kinase-A) oppose activation of the Hh pathway by regulating the stability of intermediate signaling transcription factors of Hh pathway. SuFu interacts directly with CI proteins, repressing Hh signaling. In the absence of Hh signal, Cos2 and SuFu binding to CI, prevent CI activation and retain it in the cytoplasm. Most of CI is available for cleavage in a process which is dependent upon its phosphorylation by the AC (Adenylate Cyclase) induced PKA and which involves Cos2, Slimb and GSK3H. Uncleaved, full-length CI is actively exported from the nucleus. Again Hh reception activates Fu, which in turn acts on Cos2 and SuFu , alleviating their negative effect on CI. As a result, CI cleavage is reduced, CI155 nuclear import overcomes its export and CI is activated. CI activation requires Cos2 and Fu  to antagonize SuFu negative effect. It is obvious that Cos2, Fu and SuFu play multiple and complex roles in CI control. Cos2 is central to this control both as a negative regulator in the absence of Hh and a positive regulator in the presence of Hh. In the absence of Hh signal, Cos2 action prevents CI target activation by favoring CI cleavage and by cytoplasmic retention of full-length CI. In response to Hh, Cos2 is also required for complete CI activation in the wing imaginal disc. Fu  is also involved in positive and negative aspects of CI regulation. Its kinase activity is required for CI cytoplasmic release and activation in response to Hh signal. Its C-terminal regulatory domain that is required for Fu  kinase activity cooperates with Cos2 and SuFu to negatively regulate CI in the absence of Hh signal. Activated nuclear CI155 activates the transcription of Hh target genes like WNT, Ptc and Dpp (Decapentaplegic) (Ref.4 & 5). The WNTs function to maintain homeostasis, Ptc acts as the pathway suppressor, whereas, the stable and precise positioning of the Dpp morphogen source is crucial for growth and patterning of the entire wing. In general, the Hedgehog signaling in Drosophila accounts for the continuous segregation of cells into compartments and is crucial for the positioning and maintenance of such organizers for the precise implementation of body plans (Ref.6).