Outlines of Hedgehog signaling
Hedgehog family of signaling proteins are pivotal for growth, patterning, and morphogenesis during embryonic development of vertebrates and many invertebrates. The hedgehog signaling pathway is one of the key regulators of animal development conserved from flies to humans. The Drosophila hedgehog gene was identified as one of several genes important for creating the differences between the anterior and posterior parts of individual body segments in the famous genetic screen of Nusslein-Volhard and Eric Wieschaus during late 70’s. It was named Hedgehog because a larva which lacked this protein completely ( a mutant), looked very spiky and resembled a hedgehog. In Biological science its a normal practice that if one happen to identify a novel gene , then the discoverer can assign a name of his/her choice to it. That could be reason why we have some very funny names ( but makes sense according to phenotype) for Drosophila genes eg : Painless , Heartless, mother against dpp, twin of eyeless, daughterless and so on.
The signal of Hedgehog mostly act as morphogen in a concentration dependent manner activating distinct cell fates within a target tissue, or as inducing factors controlling the form of a developing organ.
In Drosophila basic outline includes a receptor (patched) and signaling is initiated upon binding of hedgehog (ligand). Smoothened (Smo) is a seven-transmembrane domain protein that is a key link between Ptc and the rest of the transduction complex, which comprises the transcription factor Cubitus interruptus (Ci), the serine/threonine kinase Fused (Fu), the kinesin-like molecule Costal 2 (Cos2) and Supressor of fused (Sufu). Smo associates physically with other transduction complex components through binding to Cos2 (costal-2). Ptc acts as an inhibitor of smo and in absence of hedgehog signal , Ci is cleaved into repressor form and hence transcription of hedgehog target genes is prevented. However in presence of hedgehog signal the inhibitory effects of Ptc on Smo are relieved. Smo becomes phosphorylated preventing the cleavage of Ci.
This full length Ci is goes into nucleus and induce the transcription of Hedgehog target genes.
In vertebrates there are three hedgehogs : Sonic, Indian and Desert Hedgehog. There are also two Ptc genes (Ptc 1 and Ptc 2) as well as three Ci homologues known as Gli 1, Gli 2 and Gli 3. Gli1 and Gli2 are transcriptional activators, whereas Gli 3 functions as a transcriptional repressor. Its is believed that signaling downstream of Smoothened has been significantly diverged between invertebrates and vertebrates. The role of Suppressor of Fused (SUFU) has been enhanced in vertebrates compared to Drosophila where its role is relatively minor. Costal-2 is particularly important in Drosophila. The protein kinase Fused is a regulator of SUFU in Drosophila, but may not play a role in the Hh pathway of vertebrates. Another important difference is that in vertebrates, Hh signalling has been heavily coupled to cilia.
The cilium, a microtubule-based organelle, is present on the surface of most vertebrate cells. Studies done both in vivo and invitro has shown involvement of cilia in wingless and hedgehog signaling ( Haycraft et al., 2005 ) for the function or generation of both Gli activator and repressor activity. In the absence of cilia, Gli2 activator can’t function and Gli3 processing is heavily compromised. Interestingly cilia are not required for normal functioning of hedgehog and wingless signaling in Drosophila even though most components of these signaling pathways are conserved from fruit flies to humans.
Finally to gain some insights on how hedgehog signalling has evolved , check out a review by Konrad basler in Plos one
References :
Nusslein-Volhard C., Wieschaus E. (1980) Mutations affecting segment number and polarity in Drosophila. Nature. 287, 795-801.
Hooper, JE and MP Scott (2005) Communicating with Hedgehogs. Nature Reviews in Mol Cell Biol 6:304-317..
A nice overview at wikipedia
The Primary Cilium as a Complex Signaling Center ( A review)
Berbari NF, O’Connor AK, Haycraft CJ, Yoder BK.
Curr Biol. 2009 Jul 14;19(13):R526-35.
The Hedgehog Signaling Pathway: Where Did It Come From?
Hausmann G, von Mering C, Basler K (2009)
PLoS Biol 7(6): e1000146. doi:10.1371/journal.pbio.1000146
Important Hedgehog labs :
Matthew Scott at HHMI –Cholesterol, Embryonic development, and Disease
Philip Beachy Profile Stanford –Hedgehog Signaling in Development and Disease
Phil Ingham @ IMCB , Singapore
Konrad Basler @ ZTH , Zurich
Image Credit : wikimedia commons
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