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WIREs Dev Biol
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Primary cilia and graded Sonic Hedgehog signaling

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Abstract Cilia are evolutionary‐conserved microtubule‐containing organelles protruding from the surface of cells. They are classified into two types—primary and motile cilia. Primary cilia are nearly ubiquitous, at least in vertebrate cells, and it has become apparent that they play an essential role in the intracellular transduction of a range of stimuli. Most notable among these is Sonic Hedgehog. In this article we briefly summarize the structure and biogenesis of primary cilia. We discuss the evidence implicating cilia in the transduction of extrinsic signals. We focus on the involvement and molecular mechanism of cilia in signaling by Sonic Hedgehog in embryonic tissues, specifically the neural tube, and we discuss how cilia play an active role in the interpretation of gradients of Sonic Hedgehog (Shh) signaling. WIREs Dev Biol 2012. doi: 10.1002/wdev.43 For further resources related to this article, please visit the WIREs website.

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Primary and motile cilia. (a) Cross section of the axoneme of motile and primary cilia. Primary cilia can be divided into two groups—immotile primary cilia and nodal cilia. Nodal cilia have axonemal dynein arms. In all cases the diameter of the axoneme is 200–250 nm. (b) The structure of primary cilia. In the ciliary shaft, anterograde transport depends on Kinesin‐II motor proteins—the heterotrimeric complex of KIF3A, KIF3B, and the Kif‐associated Protein KAP3, or the homodimeric complex of KIF17—and intraflagellar transport (IFT)‐B proteins. Retrograde transport depends on the dynein proteins, dync2h1 and dync2l1 and IFT‐A complex proteins. The transition zone separates the axoneme and the basal body from the rest of the cell and functions as a diffusion barrier. In addition to several proteins that localize to this area, the lipid composition and the vesicles associated with BBS proteins are involved in sorting the proteins that enter the cilia. The basal body is formed from the mother centriole, generated in the previous cell cycle, and is connected to the daughter centriole.3,12–15

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Classification of the neural tube phenotype in mutant mice lacking Shh‐related ciliary factors. The left panel illustrates the dorsal–ventral pattern of a cross section of the neural tube. Each of the interneuron subtypes (v0–v3) and motor neurons (MNs) differentiate from their adjacent progenitor domains (p0–p3, pMN), located at a characteristic dorsal–ventral position. Each progenitor domain is defined by the combination of transcription factors it expresses and is established by a gradient of Shh emanating from the ventrally located floor plate and notochord. The right panels categorize the patterning defects observed in the neural tube and indicate the mutated genes that produce these phenotypes. In Categories I and II defects the generation of ventral identities is lost or decreased, these phenotypes suggest the reduction of Shh signaling activity. Conversely, Categories III and IV defects display phenotypes in which ventral identities are expanded dorsally. This is due to increased GliAct and to a loss of negative regulation of Shh signaling leading to decreased GliRep. Slanted blocks represent a mixture of cell identities. Underneath each diagram are lists of the mutants that fall into these categories. pDI; dorsal interneuron progenitors, RP; roof plate, FP; floor plate.

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The Hedgehog signaling pathway and cilia. In the absence of the Hedgehog ligand, the receptor protein Ptc is localized to cilia and inhibits another membrane protein Smo from residing in the cilia. Full‐length Gli2 and Gli3 proteins (yellow GliFL) bind to SuFu and KIF7. GliFL proteins transit through the cilia. This results in GliFL acquiring an as yet to be determined mark (green GliFL). The marked GliFL is phosphorylated by PKA‐CK1‐GSK3β (orange GliFL) probably at the base of the cilia and GliFL is processed, by β‐TrCP and Cul3, to form the truncated repressor form of Gli (red GliRep). GliRep dissociates from SuFu and enters the nucleus to repress target genes. In the presence of Hedgehog, Ptc leaves cilia, which allows the activation of Smo. Two kinases GRK2 and β‐Arr2 phosphorylate the carboxy‐terminal serine residues of Smo facilitating the activation of Smo. Activated Smo enters and resides in the ciliary membrane. The complex of GliFL and SuFu dissociates in the cilia, and the free GliFL, now in its activator form (GliAct) translocates into the nucleus. GliAct is phosphorylated and the degradation of GliFLand GliAct is mediated by the ubiquitin ligase SPOP.

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Nervous System Development > Vertebrates: General Principles
Establishment of Spatial and Temporal Patterns > Gradients
Signaling Pathways > Global Signaling Mechanisms