Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Sonic Hedgehog (Shh)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_102

Historical Background

The Hedgehog (Hh) family of secreted proteins plays an essential role in metazoan development, and defects in the Hh pathway lead to congenital abnormalities such as holoprosencephaly and certain forms of cancer. The importance of Hh during embryogenesis was first discovered in a genetic screen for mutations disrupting larval patterning in Drosophila melanogaster by Nusslein-Volhard and Wieschaus in 1980 (Varjosalo and Taipale 2008). Unlike Drosophila, which harbors a single Hh gene, the mammalian genome encodes three Hh ligands: Dessert Hedgehog (Dhh), Indian Hedgehog (Ihh), and Sonic Hedgehog (Shh), all of which activate the vertebrate Hh pathway in a similar manner. Shh is the most widely expressed of these ligands, and much of what is known about vertebrate Hh signaling stems from studies on Shh. Though similar in many ways to the Drosophila Hh pathway, several features of vertebrate Hh signaling make it unique. Perhaps the most striking divergence is in the role that the primary cilium, a vestigial organelle that is largely absent in flies, plays in vertebrate Hh signaling. Over the past two decades considerable process has been made in understanding vertebrate Hh signaling and Shh in particular. Nonetheless, why the primary cilium plays such a central role in the vertebrate pathway is one of several unanswered questions requiring further inquiry and exploration. Thus, in addition to summarizing the current understanding of Shh signaling, this entry will also introduce unanswered questions and remaining areas of ambiguity.

Sonic Hedgehog Processing and Release

Hedgehog proteins undergo a unique series of posttranslational processing steps that result in the covalent attachment of two lipid moieties: cholesterol at the C-terminus and palmitate at the N-terminus. Shown in Fig. 1, Shh is synthesized as a 45 kD precursor molecule in the endoplasmic reticulum. Following removal of its signal sequence, Shh undergoes a cholesterol-dependent autocatalytic cleavage, generating two peptides roughly equal in size (Varjosalo and Taipale 2008). The C-terminal fragment has no known signaling function and undergoes ER-associated degradation (ERAD), a process that requires the ubiquitin ligase Hrd1 and its partner Sel1 as well as the ATPase p97 (Chen et al. 2011). The N-terminal fragment ultimately gives rise to the dually lipidated mature signaling molecule. A cholesterol moiety is added to its C-terminus during the aforementioned cleavage event, and Hh acyltransferase (Hhat) catalyzes the attachment of a palmitate moiety at the N-terminus (Varjosalo and Taipale 2008). Dually lipidated Shh is targeted to the cell surface through the secretory pathway.
Sonic Hedgehog (Shh), Fig. 1

Shh processing and release. Shh is synthesized as a 45 kDa precursor in the endoplasmic reticulum. (1) An autocatalytic cleavage event results in the formation of C- and N-terminal fragments. The cholesterol-modified N-terminal fragment enters the secretory pathway and ultimately serves as the mature signaling ligand, whereas (2) the C-terminal fragment is degraded via ER-associated degradation (ERAD). (3) Hh acyltransferase (Hhat) catalyzes the covalent attachment of palmitate to the N-terminus of the N-terminal fragment. Dually lipidated Shh is targeted to the cell membrane where (4) Heparan sulfate proteoglycans (HSPG) facilitate the formation of Shh multimers. Multimeric Shh is secreted via (5) A disintegrase and metalloproteases (ADAM) and the (6) 12-pass transmembrane protein Dispatched1 (Disp1)

While the process of cholesterol and palmitate attachment to Shh is relatively well-defined, the functional significance of these modifications is more complex. One of the key features of Shh is its ability to signal over long distances, and cholesterol was originally thought to promote such long-range signaling (Lewis et al. 2001). However, initial studies relied upon a mouse model in which Shh expression was severely impaired, and additional studies showed that cholesterol restricts, rather than promotes, the spread of Shh (Li et al. 2006). By contrast, palmitoylation appears to primarily affect the potency of Shh, as mouse mutants producing a non-palmitoylated form of Shh have significantly reduced levels of Shh pathway activity (Chen et al. 2004). Recent studies in vitro indicate that the palmitate moiety promotes the formation of active Shh oligomers by facilitating the cleavage of N-terminal peptides that otherwise obstruct important receptor binding sites in multimeric Shh (Ohlig et al. 2011). This cleavage is mediated by A disintegrase and metalloproteases (ADAMs), which remove the palmitate moiety and adjacent amino acids before Shh is released (Ohlig et al. 2011). In the absence of palmitoylation, either due to loss of Hhat or to mutations in the N-terminal cysteine residue where palmitate attaches, this cleavage cannot occur and the resulting multimer is far less potent. Cholesterol also plays an essential role in multimer formation, as Shh lacking cholesterol (ShhN) is secreted solely as monomers (Guerrero and Chiang 2007). Cholesterol may promote multimer formation by tethering Shh to the plasma membrane, allowing negatively charged heparan sulfate proteoglycans (HSPG) to bind positively charged residues in the Cardin Wientraub (CW) motif and cluster Shh on the membrane (Dierker et al. 2009). Taken together, these data provide insight into why Shh receives such unusual posttranslational modifications in order to properly function.

The covalent attachment of cholesterol and palmitate render Shh membrane-tethered, and the release of lipid-modified Shh into the extracellular environment requires the activity of the 12-pass transmembrane protein Dispatched1. Mouse Disp1 mutants die around embryonic day 9.5 with severe defects in the Shh pathway, indicating that Disp1 plays an essential role in vertebrate Hh signaling (Caspary et al. 2002; Kawakami et al. 2002; Ma et al. 2002). Cells lacking Disp1 synthesize and process Shh normally, but are unable to secrete the mature ligand. Instead, Shh accumulates on the plasma membrane of Disp1 -/- cells, able to signal to neighboring cells but unable to signal distally (Ingham et al. 2011). In addition to Disp1, recent in vitro work suggests that ADAMs may also facilitate Shh secretion by cleaving both lipid moieties, rendering the secreted form of Shh unlipidated (Dierker et al. 2009; Ohlig et al. 2011). Nonetheless, the importance of ADAM-mediated cleavage in vivo has not been shown, nor has whether ADAMs interact and cooperate with Disp1 to facilitate Shh secretion. Addressing these two questions will help complete the story of how Shh is released from producing cells.

Cytosolic Sonic Hedgehog Signaling


The core components of Drosophila Hh signaling are conserved in vertebrates. Shh-producing cells secrete Shh, which binds Patched1 (Ptch1), a 12-pass transmembrane protein that serves as the Shh receptor. Binding of Shh to Ptch1 relieves Ptch1-mediated inhibition of the signal transducer Smoothened (Smo), and Smo activates the zinc finger transcription factors Gli2 and Gli3, which translocate into the nucleus and promote the transcription of Shh target genes. In the absence of Shh, these transcription factors are partially processed into N-terminal transcriptional repressors that suppress the transcription of Shh targets. Thus, the relative abundance of transcriptional activators and inhibitors ultimately regulates the transcription of Shh target genes.

The Primary Cilium

Although many aspects of Drosophila Hh signaling are conserved in vertebrates, vertebrate Hh signaling depends upon the primary cilium. Primary cilia are slim, microtubule-based nonmotile structures projecting from the cell surface of nearly all vertebrate cell types. The assembly and maintenance of primary cilia requires intraflagellar transport (IFT) proteins, and several members of the IFT family are essential for proper Shh signaling (Goetz and Anderson 2010). Mutations in components of the IFT-B complex, which mediates the anterograde transport of molecules from the base of the cilium to the tip, lead to a complete loss of Shh signaling. By contrast, mutations in members of the IFT-A complex, which controls retrograde transport, lead to unkempt Shh pathway activation (Goetz and Anderson 2010). Nonetheless, it not currently known whether IFT-A and -B complexes interact directly with Shh pathway components to control their localization and activity or if, instead, these complexes facilitate Shh signaling simply by maintaining proper cilia architecture. Indeed, recent genetic studies suggest that the primary cilium may function primarily as a scaffold for Shh signaling, arguing against a direct role for IFT proteins in the movement of Shh pathway components (Ocbina et al. 2011).

Cytosolic Shh Signaling in the Absence of Ligand

Shown in Fig. 2a, in the absence of Shh ligand, Ptch1 localizes to the cilium and inhibits the seven-pass transmembrane protein Smoothened (Wilson and Chuang 2010). The precise details of this inhibition are not well understood, but may involve the transport of small molecules that maintain Smo in an inactive conformation, a possibility that is supported by the fact that Smo is susceptible to inhibition and activation by small molecules (Ingham et al. 2011). In its inactive conformation, Smo is unable to inhibit the partial proteolytic processing of the zinc finger transcription factors Gli2 and Gli3 from their full-length form into N-terminal repressors. Gli2 and Gli3 processing is facilitated by Suppressor of Fused (Sufu), which promotes the phosphorylation of Gli2 and Gli3 by Protein Kinase A (PKA), Casein Kinase I (CKI), and Glycogen Synthase Kinase ß (GSK3ß) (Humke et al. 2010; Tukachinsky et al. 2010). The Kinesin 4 family member Kif7 may also facilitate this phosphorylation. Phosphorylated Gli2 and Gli3 are recognized by the E3 ubiquitin ligase ß-TrCP, leading to the proteolytic degradation of C-terminal peptides and the formation of Gli2 and Gli3 transcriptional repressors (Gli2R and Gli3R) (Wilson and Chuang 2010). Because Gli3 is more efficiently processed than Gli2, Gli3R serves as the principle repressor of Shh signaling. These transcriptional repressors translocate into the nucleus where they suppress the transcription of Shh target genes.
Sonic Hedgehog (Shh), Fig. 2

Cytosolic Shh signaling. (a) In the absence of ligand, Ptch1 localizes to the cilium and inhibits Smo. Sufu-Gli-Kif7 complexes are phosphorylated by PKA, GSK3ß and CKI, enabling their recognition by the E3 Ubiquitin ligase ß-TrCP and resulting in the proteolytic processing of C-terminal peptides. The resulting of N-terminal transcriptional repressors (GliR) repress the transcription of Shh target genes. (b) In the presence of Shh ligand, Shh binds Ptch1-co-receptor complexes, causing them to exit the cilium. No longer inhibited by Ptch1, Smo enters the cilium by lateral transport. Activated Smo recruits and dissociates Sufu-Gli-Kif7 complexes, and additional modifications lead to the formation of transcriptional activators (GliA), which enter the nucleus and promote the transcription of Shh target genes. Spop competes with Sufu for binding to full-length Gli molecules and promotes the proteolytic degradation of Gli-FL

While Sufu has a relatively minor role in Drosophila, it is indispensible for proper Shh signaling in vertebrates (Ingham et al. 2011). Sufu-/- mice die around embryonic day 9.5, displaying aberrant Shh pathway activation and dramatically reduced levels of both full length and repressor forms of Gli, supporting a model wherein Sufu stabilizes full-length Gli and assists in GliR formation (Tukachinsky et al. 2010). Recent studies indicate that the Cul3 adaptor Speckle-type POZ protein (Spop) promotes the degradation of full-length Gli2 and Gli3 and competes with Sufu for binding of these molecules (Wang et al. 2010). Accordingly, genetic ablation of Spop from Sufu -/- cells partially rescues full-length Gli2 and Gli3 protein levels.

In addition to Sufu, the kinesin Kif7 also promotes the processing of full-length Gli and may form a complex with Gli and Sufu (Endoh-Yamagami et al. 2009; Wilson and Chuang 2010). Mice lacking functional Kif7 have reduced levels of Gli3R, increased levels of full-length Gli2, and exhibit features of aberrant Shh pathway activation such as polydactyl (Cheung et al. 2009; Endoh-Yamagami et al. 2009; Liem et al. 2009). Thus, much as its Drosophila homolog Cos2, Kif7 may serve as a scaffolding molecule for GliR production in the vertebrate Hh pathway (Wilson and Chuang 2010). However, unlike Cos2, Kif7 has a functional motor domain, and mutations in this domain impair the ability of Kif7 to promote GliR formation (Liem et al. 2009). Nonetheless, whether Kif7’s motor function influences the trafficking of Shh pathway components remains unclear, as does the precise role of Kif7 in Shh signaling.

Cytosolic Shh Signaling in the Presence of Ligand

Shown in Fig. 2b, activation of the Shh pathway results in both inhibition of Gli repressor formation and induction of Gli activator formation, ultimately leading to the transcription of Shh target genes. In the presence of Shh ligand, Shh binds Ptch1, relieving Ptch1-mediated inhibition of Smo. Smo levels increase on the plasma membrane, and Smo moves into the cilium where it promotes the disassembly of Sufu-Gli-Kif7 complexes and inhibits the proteolytic processing of Gli2 and Gli3 into their repressor forms (Milenkovic et al. 2009; Tukachinsky et al. 2010; Humke et al. 2010). Full-length Gli2 and Gil3 acquire additional poorly characterized modifications that convert them to their activator forms (Gli2A and Gli3A). Whereas Gli3 acts primarily as a transcriptional repressor, Gli2 acts primarily as a transcriptional activator. In the presence of Shh, Kif7, Smo, and Gli are enriched in the cilium tip, which may serve the location of GliA formation. Activated Gli2 induces the expression of Gli1, which acts solely as an activator of Shh signaling. In addition to inducing the transcription of genes involved in proliferation and differentiation, Gli1 and Gli2 promote the transcription of Ptch1, which inhibits further pathway activation in the absence of additional ligand.


Three membrane-associated co-receptors – Growth arrest-specific 1 (Gas1), CAM-related/downregulated by oncogenes (Cdo), and Brother of Cdo (Boc) – facilitate Shh reception and positively regulate the pathway (Beachy et al. 2010). While removal of any one of these molecules leads to a modest, tissue-specific reduction in Shh pathway activity, loss of all three co-receptors completely abolishes Shh signaling, indicating that Cdo, Boc, and Gas1 are indispensible for vertebrate Hh signaling (Allen et al. 2011; Izzi et al. 2011). These molecules likely form distinct receptor complexes with Ptch1 and enable proper Shh binding (Izzi et al. 2011). In contrast to these positive regulators of Shh signaling, Hedgehog interacting protein (Hhip) functions as a decoy receptor and serves as a negative regulator of the pathway (Beachy et al. 2010). Whereas the expression of Cdo, Boc, and Gas1 are downregulated in the presence of Shh, the expression of Hhip is upregulated, thus providing a means of tempering pathway activity.

Shh Signaling in Development and Disease

Shh functions as a morphogen, mitogen, and survival factor to regulate the development and patterning of many tissues in the vertebrate embryo. In the embryonic neural tube, for instance, floor plate-derived Shh promotes the proliferation, survival, and specification of neural progenitors. Similarly, Shh arising from the zone of proliferation (ZPA), a Shh-producing center in the posterior region of the limb bud, regulates digit specification in the embryonic limb (Jiang and Hui 2008). In the developing foregut, endoderm-derived Shh provides instructional cues to the surrounding mesoderm, resulting in proper development of both the gastrointestinal tract and lung (McMahon et al. 2003). In some tissues, the importance of Shh persists even after birth. For example, during the late embryonic and early postnatal stages, Purkinje cell-derived Shh is essential for granule cell precursor proliferation in the developing cerebellum (Jiang and Hui 2008). In the adult, Shh is required for the maintenance of stem cell populations both in the brain and the epithelium (Jiang and Hui 2008). Defects in Shh signaling have been linked to numerous congenital abnormalities, including holoprosencephaly, polydactyl, and tracheal-esophageal fistula, underscoring the importance of the pathway for normal development (McMahon et al. 2003).

Whereas loss of Shh signaling leads to congenital abnormalities, increased pathway activity has been linked to certain forms of cancer. Somatic mutations in Ptch1, the Shh receptor and a potent inhibitor of the pathway, are observed in nearly all cases of basal cell carcinoma (BCC), a common but rarely metastatic form of skin cancer (Barakat et al. 2010). Similarly, inactivating mutations in Ptch1 or activating mutations in Smo are observed in a subset of medulloblastomas (MB), a malignant tumor of the cerebellum and the most common pediatric brain tumor (Jiang and Hui 2008). Additionally, aberrant Shh pathway activity may contribute to rhabdomyosarcoma (RMS), a pediatric cancer thought to arise from skeletal muscle progenitors (Barakat et al. 2010). While aberrant pathway activation underlies BCC, MB, and RMS, other cancers such as pancreatic ductal adenocarcinoma exhibit paracrine Shh signaling, whereby tumor cells secrete Shh into the surrounding stroma and influence the tumor microenvironment (Yauch et al. 2008). Given the role of Shh signaling in oncogenesis, it is unsurprisingly that efforts have been made to target the pathway pharmacologically. Many of these agents have recently entered phase II and III clinical trials, and the efficacy of Shh inhibitors will become apparent in years to come (Ng and Curran 2011).


The most widely expressed of the three Hh ligands in mammals, Sonic Hedgehog is essential for proper embryonic development and patterning. Over the past 20 years, significant progress has been made in understanding the production, release, and downstream signaling of Shh ligands. Nonetheless, several fundamental questions regarding the pathway remain unanswered. First, a detailed understanding of how Disp1 and ADAMs mediate the secretion of multimeric Shh remains elusive. Second, the process by which Ptch1 inhibits and regulates the subcellular localization of Smo is not yet known, nor is the process by which Sufu-Gli complexes are dissociated by activated Smo. Finally, and perhaps most perplexing, is the question of how, and why, the primary cilium plays such an essential role in vertebrate Hh signal transduction. Answering these questions will not only provide insight into vertebrate development, but may inform the treatment of Hedgehog-driven tumors.


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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Cell and Developmental BiologyVanderbilt University Medical CenterNashvilleUSA