scholarly journals Mice Deficient in the Fused Homolog Do Not Exhibit Phenotypes Indicative of Perturbed Hedgehog Signaling during Embryonic Development

2005 ◽  
Vol 25 (16) ◽  
pp. 7042-7053 ◽  
Author(s):  
Miao-Hsueh Chen ◽  
Nan Gao ◽  
Takatoshi Kawakami ◽  
Pao-Tien Chuang
Keyword(s):  
Signal Transduction ◽  
Embryonic Development ◽  
Hedgehog Signaling ◽  
Gene Activation ◽  
Genetic Studies ◽  
Suppressor Of Fused ◽  
Gli Transcription Factors ◽  
Processing Activity ◽  
Hh Signaling ◽  
Deficient Mice

ABSTRACT Hedgehog (Hh) signaling plays a major role in multiple aspects of embryonic development. To understand how a single Hh signal is capable of generating distinct readouts in Hh-responsive cells requires elucidation of the signal transduction cascade at the molecular level. Key components that mediate Hh signal transduction downstream of the receptor include Fused (Fu), Suppressor of fused (Sufu), and Costal-2 (Cos2) or the vertebrate homologs Kif27/Kif7. Studies with both invertebrates and vertebrates have led to a model in which a protein complex composed of Fu, Sufu, and Cos2 controls the processing, activity, and subcellular distribution of the Ci/Gli transcription factors responsible for Hh target gene activation. These converging results obtained with different species reaffirm the prevailing view of pathway conservation during evolution. Genetic studies of Fu, Sufu, and Kif27/Kif7 in mice are required to provide further verification of Hh pathway conservation. To this end, we generated a gene-targeted allele of Fu in mice. Surprisingly, our analysis indicates that Fu-deficient mice do not exhibit any embryonic phenotypes indicative of perturbed Hh signaling. This could be due to either functional redundancy or Hh pathway divergence and clearly indicates greater complexity of Hh signaling in vertebrates.

scholarly journals Hedgehog Signaling in Skeletal Development: Roles of Indian Hedgehog and the Mode of Its Action

2020 ◽  
Vol 21 (18) ◽  
pp. 6665 ◽  
Author(s):  
Shinsuke Ohba
Keyword(s):  
Hedgehog Signaling ◽  
Feedback Loop ◽  
Skeletal Development ◽  
Indian Hedgehog ◽  
Growth Plate Chondrocytes ◽  
Chondrocyte Proliferation ◽  
Genetic Studies ◽  
Parathyroid Hormone Related Protein ◽  
Gli Transcription Factors ◽  
Hh Signaling

Hedgehog (Hh) signaling is highly conserved among species and plays indispensable roles in various developmental processes. There are three Hh members in mammals; one of them, Indian hedgehog (Ihh), is expressed in prehypertrophic and hypertrophic chondrocytes during endochondral ossification. Based on mouse genetic studies, three major functions of Ihh have been proposed: (1) Regulation of chondrocyte differentiation via a negative feedback loop formed together with parathyroid hormone-related protein (PTHrP), (2) promotion of chondrocyte proliferation, and (3) specification of bone-forming osteoblasts. Gli transcription factors mediate the major aspect of Hh signaling in this context. Gli3 has dominant roles in the growth plate chondrocytes, whereas Gli1, Gli2, and Gli3 collectively mediate biological functions of Hh signaling in osteoblast specification. Recent studies have also highlighted postnatal roles of the signaling in maintenance and repair of skeletal tissues.

scholarly journals The role of the Hedgehog signaling pathway in cancer: A comprehensive review

2018 ◽  
Vol 18 (1) ◽  
pp. 8-20 ◽  
Author(s):  
Ana Marija Skoda ◽  
Dora Simovic ◽  
Valentina Karin ◽  
Vedran Kardum ◽  
Semir Vranic ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Signaling Pathway ◽  
Hedgehog Signaling ◽  
Target Genes ◽  
Biological Effects ◽  
Signal Transmission ◽  
Adenosine Monophosphate ◽  
Evolutionary Pathway ◽  
Gli Transcription Factors ◽  
Hh Signaling

The Hedgehog (Hh) signaling pathway was first identified in the common fruit fly. It is a highly conserved evolutionary pathway of signal transmission from the cell membrane to the nucleus. The Hh signaling pathway plays an important role in the embryonic development. It exerts its biological effects through a signaling cascade that culminates in a change of balance between activator and repressor forms of glioma-associated oncogene (Gli) transcription factors. The components of the Hh signaling pathway involved in the signaling transfer to the Gli transcription factors include Hedgehog ligands (Sonic Hh [SHh], Indian Hh [IHh], and Desert Hh [DHh]), Patched receptor (Ptch1, Ptch2), Smoothened receptor (Smo), Suppressor of fused homolog (Sufu), kinesin protein Kif7, protein kinase A (PKA), and cyclic adenosine monophosphate (cAMP). The activator form of Gli travels to the nucleus and stimulates the transcription of the target genes by binding to their promoters. The main target genes of the Hh signaling pathway are PTCH1, PTCH2, and GLI1. Deregulation of the Hh signaling pathway is associated with developmental anomalies and cancer, including Gorlin syndrome, and sporadic cancers, such as basal cell carcinoma, medulloblastoma, pancreatic, breast, colon, ovarian, and small-cell lung carcinomas. The aberrant activation of the Hh signaling pathway is caused by mutations in the related genes (ligand-independent signaling) or by the excessive expression of the Hh signaling molecules (ligand-dependent signaling – autocrine or paracrine). Several Hh signaling pathway inhibitors, such as vismodegib and sonidegib, have been developed for cancer treatment. These drugs are regarded as promising cancer therapies, especially for patients with refractory/advanced cancers.

scholarly journals Hedgehog Signaling in Colorectal Cancer: All in the Stroma?

2021 ◽  
Vol 22 (3) ◽  
pp. 1025
Author(s):  
Natalie Geyer ◽  
Marco Gerling
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressors ◽  
Hedgehog Signaling ◽  
Current Knowledge ◽  
Intestinal Development ◽  
Immunomodulatory Effects ◽  
Gli Transcription Factors ◽  
Hh Signaling ◽  
Potential Impact

Hedgehog (Hh) signaling regulates intestinal development and homeostasis. The role of Hh signaling in cancer has been studied for many years; however, its role in colorectal cancer (CRC) remains controversial. It has become increasingly clear that the “canonical” Hh pathway, in which ligand binding to the receptor PTCH1 initiates a signaling cascade that culminates in the activation of the GLI transcription factors, is mainly organized in a paracrine manner, both in the healthy colon and in CRC. Such canonical Hh signals largely act as tumor suppressors. In addition, stromal Hh signaling has complex immunomodulatory effects in the intestine with a potential impact on carcinogenesis. In contrast, non-canonical Hh activation may have tumor-promoting roles in a subset of CRC tumor cells. In this review, we attempt to summarize the current knowledge of the Hh pathway in CRC, with a focus on the tumor-suppressive role of canonical Hh signaling in the stroma. Despite discouraging results from clinical trials using Hh inhibitors in CRC and other solid cancers, we argue that a more granular understanding of Hh signaling might allow the exploitation of this key morphogenic pathway for cancer therapy in the future.

Hedgehog signaling and the axial patterning of Drosophila wings

2000 ◽  
Vol 78 (5) ◽  
pp. 585-591 ◽  
Author(s):  
William J Brook
Keyword(s):  
Signal Transduction ◽  
Cell Fate ◽  
Limb Development ◽  
Hedgehog Signaling ◽  
Post Translational Modification ◽  
Cubitus Interruptus ◽  
Axial Patterning ◽  
Correct Location ◽  
Hh Signaling ◽  
Anterior Posterior

Growth and cell fate in the anterior-posterior (A/P) axis of the developing wing of Drosophila melanogaster are controlled by a stripe of cells bisecting the axis called the A/P organizer. Hedgehog (Hh) signaling from posterior to anterior cells induces the organizer. Several Hh-responsive genes expressed by cells of the organizer mediate its patterning activity. The Hh-signaling pathway controls the post-translational modification of the transcription factor Cubitus-interruptus (Ci) and the resulting local activation of Ci is required for the correct location of the A/P organizer.Key words: Hedgehog, morphogen, Drosophila, limb development, signal transduction.

scholarly journals DYRK2 is a ciliary kinase involved in vertebrate Hedgehog signal transduction

2020 ◽  
Author(s):  
Nicholas Morante ◽  
Monika Abedin Sigg ◽  
Luke Strauskulage ◽  
David R. Raleigh ◽  
Jeremy F. Reiter
Keyword(s):  
Signal Transduction ◽  
Transcription Factors ◽  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Skeletal Development ◽  
Skeletal Defects ◽  
Gli Transcription Factors ◽  
Hedgehog Signal Transduction ◽  
Hedgehog Signal

ABSTRACTPrimary cilia are organelles specialized for signaling. We previously defined the proteomes of sea urchin and sea anemone cilia to identify ciliary proteins that predate the origin of bilateria. This evolutionary perspective on cilia identified DYRK2, a kinase not been previously implicated in ciliary biology. We found that DYRK2 localizes to cilia and that loss of DYRK2 disrupts ciliary morphology. We also found that DYRK2 participates in ciliary Hh signal transduction, communicating between SMO and GLI transcription factors. Mutation of mouse Dyrk2 resulted in skeletal defects reminiscent of those caused by loss of Indian hedgehog (Ihh). Like Dyrk2 mutations, pharmacological inhibition of DYRK2 dysregulates ciliary length control and attenuates Hedgehog signaling. Thus, DYRK2 is required for ciliary morphology, for Hedgehog signaling in vitro, and for skeletal development. We propose that DYRK2 is part of the mechanism that transduces SMO to activate GLI transcription factors within cilia.

scholarly journals An absolute requirement for Cubitus interruptus in Hedgehog signaling

Development ◽  
2001 ◽  
Vol 128 (5) ◽  
pp. 733-742 ◽  
Author(s):  
N. Methot ◽  
K. Basler
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Hedgehog Signaling ◽  
Target Gene ◽  
Target Genes ◽  
Signal Transduction Pathway ◽  
Transduction Pathway ◽  
Cubitus Interruptus ◽  
Target Gene Expression ◽  
Hh Signaling

Hedgehog (Hh) proteins play diverse organizing roles in animal development by regulating gene expression in responding cells. Several components of the Hh signal transduction pathway have been identified, yet their precise role in mediating the various outputs of the pathway is still poorly understood. The Gli homolog Cubitus interruptus (Ci) is involved in controlling the transcription of Drosophila Hh target genes and thus represents the most downstream component known in this pathway. We address the question of whether the Hh pathway is distally branched or, in other words, whether the regulation of Ci activity is the sole output of Hh signaling. Putative Ci-independent branches of Hh signaling are explored by analyzing the behavior of cells that lack Ci but have undergone maximal activation of the Hh transduction pathway due to the removal of Patched (Ptc). The analysis of target gene expression and morphogenetic read-outs of Hh in embryonic, larval and adult stages indicates that Ci is absolutely required for all examined aspects of Hh outputs. We interpret this as evidence against the existence of Ci-independent branches in the Hh signal transduction pathway and propose that most cases of apparent Ci/Gli-independent Hh output can be attributed to the derepression of target gene expression in the absence of Ci/Gli repressor function.

scholarly journals Competition between two phosphatases fine-tunes Hedgehog signaling

2020 ◽  
Vol 220 (2) ◽  
Author(s):  
Min Liu ◽  
Aiguo Liu ◽  
Jie Wang ◽  
Yansong Zhang ◽  
Yajuan Li ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Phosphatase Activity ◽  
Protein Phosphatase ◽  
Hedgehog Signaling ◽  
Catalytic Subunit ◽  
Regulatory Subunit ◽  
Feedback Mechanisms ◽  
Hh Signaling ◽  
High Level ◽  
Signaling Activity

Hedgehog (Hh) signaling is essential for embryonic development and adult homeostasis. How its signaling activity is fine-tuned in response to fluctuated Hh gradient is less known. Here, we identify protein phosphatase V (PpV), the catalytic subunit of protein phosphatase 6, as a homeostatic regulator of Hh signaling. PpV is genetically upstream of widerborst (wdb), which encodes a regulatory subunit of PP2A that modulates high-level Hh signaling. We show that PpV negatively regulates Wdb stability independent of phosphatase activity of PpV, by competing with the catalytic subunit of PP2A for Wdb association, leading to Wdb ubiquitination and subsequent proteasomal degradation. Thus, regulated Wdb stability, maintained through competition between two closely related phosphatases, ensures graded Hh signaling. Interestingly, PpV expression is regulated by Hh signaling. Therefore, PpV functions as a Hh activity sensor that regulates Wdb-mediated PP2A activity through feedback mechanisms to maintain Hh signaling homeostasis.

scholarly journals A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu–Gli protein complexes

2010 ◽  
Vol 191 (2) ◽  
pp. 415-428 ◽  
Author(s):  
Hanna Tukachinsky ◽  
Lyle V. Lopez ◽  
Adrian Salic
Keyword(s):  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Protein Complexes ◽  
Transcription Activation ◽  
Cytoplasmic Protein ◽  
Suppressor Of Fused ◽  
Gli Proteins ◽  
Hh Signaling ◽  
Ciliary Localization ◽  
Kinase A

In vertebrates, Hedgehog (Hh) signaling initiated in primary cilia activates the membrane protein Smoothened (Smo) and leads to activation of Gli proteins, the transcriptional effectors of the pathway. In the absence of signaling, Gli proteins are inhibited by the cytoplasmic protein Suppressor of Fused (SuFu). It is unclear how Hh activates Gli and whether it directly regulates SuFu. We find that Hh stimulation quickly recruits endogenous SuFu–Gli complexes to cilia, suggesting a model in which Smo activates Gli by relieving inhibition by SuFu. In support of this model, we find that Hh causes rapid dissociation of the SuFu–Gli complex, thus allowing Gli to enter the nucleus and activate transcription. Activation of protein kinase A (PKA), an inhibitor of Hh signaling, blocks ciliary localization of SuFu–Gli complexes, which in turn prevents their dissociation by signaling. Our results support a simple mechanism in which Hh signals at vertebrate cilia cause dissociation of inactive SuFu–Gli complexes, a process inhibited by PKA.

scholarly journals Sonic hedgehog negatively regulates pre-TCR–induced differentiation by a Gli2-dependent mechanism

Blood ◽  
2009 ◽  
Vol 113 (21) ◽  
pp. 5144-5156 ◽  
Author(s):  
Nicola J. Rowbotham ◽  
Ariadne L. Hager-Theodorides ◽  
Anna L. Furmanski ◽  
Susan E. Ross ◽  
Susan V. Outram ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Negative Regulator ◽  
Double Positive ◽  
Induced Differentiation ◽  
Transgenic Expression ◽  
Tcr Signal Transduction ◽  
Hh Signaling ◽  
Dependent Mechanism

Abstract Hedgehog signaling regulates differentiation, survival, and proliferation of the earliest double-negative (DN) thymocytes, but its importance at later stages of T-cell development is controversial. Here we use loss- and gain-of-function mouse models to show that Shh, by signaling directly to the developing thymocyte, is a negative regulator of pre-TCR–induced differentiation from DN to double-positive (DP) cell. When hedgehog signaling was reduced, in the Shh−/− and Gli2−/− thymus, or by T lineage–specific transgenic expression of a transcriptional-repressor form of Gli2 (Gli2ΔC2), differentiation to DP cell after pre-TCR signal transduction was increased. In contrast, when Hh signaling was constitutively activated in thymocytes, by transgenic expression of a constitutive transcriptional-activator form of Gli2 (Gli2ΔN2), the production of DP cells was decreased. Gene expression profiling showed that physiologic Hh signaling in thymocytes maintains expression of the transcription factor FoxA2 on pre-TCR signal transduction.

Novel pathway for thyroid hormone receptor action through interaction with jun and fos oncogene activities

1991 ◽  
Vol 11 (12) ◽  
pp. 6016-6025
Author(s):  
X K Zhang ◽  
K N Wills ◽  
M Husmann ◽  
T Hermann ◽  
M Pfahl
Keyword(s):  
Signal Transduction ◽  
Dna Binding ◽  
Thyroid Hormone Receptor ◽  
Gene Activation ◽  
Signal Transduction Pathway ◽  
Large Family ◽  
Transduction Pathway ◽  
Regulatory Pathway

Many essential biological pathways, including cell growth, development, and metabolism, are regulated by thyroid hormones (THs). TH action is mediated by intracellular receptors that belong to a large family of ligand-dependent transcription factors, including the steroid hormone and retinoic acid receptors. So far it has been assumed that TH receptors (TRs) regulate gene transcription only through the classical protein-DNA interaction mechanism. Here we provide evidence for a regulatory pathway that allows cross-talk between TRs and the signal transduction pathway used by many growth factors, oncogenes, and tumor promoters. In transient transfection studies, we observed that the oncogenes c-jun and c-fos inhibit TR activities, while TRs inhibit induction of the c-fos promoter and repress AP-1 site-dependent gene activation. A truncated TR that lacks only 17 amino acids from the carboxy terminus can no longer antagonize AP-1 activity. The cross-regulation between TRs and the signal transduction pathway appears to be based on the ability of TRs to inhibit DNA binding of the transcription factor AP-1 in the presence of THs. The constituents of AP-1, c-Jun, and c-Fos, vice versa, can inhibit TR-induced gene activation in vivo, and c-Jun inhibits TR DNA binding in vitro. This novel regulatory pathway is likely to play a major role in growth control and differentiation by THs.

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