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 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 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.

scholarly journals Organization of the Indian hedgehog – parathyroid hormone-related protein system in the postnatal growth plate

2011 ◽  
Vol 47 (1) ◽  
pp. 99-107 ◽  
Author(s):  
Michael Chau ◽  
Patricia Forcinito ◽  
Anenisia C Andrade ◽  
Anita Hegde ◽  
Sohyun Ahn ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Growth Plate ◽  
Feedback Loop ◽  
Postnatal Growth ◽  
Indian Hedgehog ◽  
Related Protein ◽  
Functional Changes ◽  
Growth Cartilage ◽  
Embryonic Growth ◽  
Parathyroid Hormone Related Protein

In embryonic growth cartilage, Indian hedgehog (Ihh) and parathyroid hormone-related protein (PTHrP) participate in a negative feedback loop that regulates chondrocyte differentiation. Postnatally, this region undergoes major structural and functional changes. To explore the organization of the Ihh–PTHrP system in postnatal growth plate, we microdissected growth plates of 7-day-old rats into their constituent zones and assessed expression of genes participating in the Ihh–PTHrP feedback loop.Ihh, Patched 1, Smoothened,Gli1, Gli2, Gli3, andPthr1were expressed in regions analogous to the expression domains in embryonic growth cartilage. However, PTHrP was expressed in resting zone cartilage, a site that differs from the embryonic source, the periarticular cells. We then used mice in whichlacZhas replaced coding sequences ofGli1and thus serves as a marker for active hedgehog signaling. At 1, 4, 8, and 12 weeks of age,lacZexpression was detected in a pattern analogous to that of embryonic cartilage. The findings support the hypothesis that the embryonic Ihh–PTHrP feedback loop is maintained in the postnatal growth plate except that the source of PTHrP has shifted to a more proximal location in the resting zone.

scholarly journals Growth Plate Chondrocytes: Skeletal Development, Growth and Beyond

2019 ◽  
Vol 20 (23) ◽  
pp. 6009 ◽  
Author(s):  
Shawn A. Hallett ◽  
Wanida Ono ◽  
Noriaki Ono
Keyword(s):  
Growth Plate ◽  
Bone Marrow Stromal Cells ◽  
Skeletal Development ◽  
Cell Types ◽  
Postnatal Growth ◽  
Lineage Tracing ◽  
Molecular Characteristics ◽  
Growth Plate Chondrocytes ◽  
Parathyroid Hormone Related Protein

Growth plate chondrocytes play central roles in the proper development and growth of endochondral bones. Particularly, a population of chondrocytes in the resting zone expressing parathyroid hormone-related protein (PTHrP) is now recognized as skeletal stem cells, defined by their ability to undergo self-renewal and clonally give rise to columnar chondrocytes in the postnatal growth plate. These chondrocytes also possess the ability to differentiate into a multitude of cell types including osteoblasts and bone marrow stromal cells during skeletal development. Using single-cell transcriptomic approaches and in vivo lineage tracing technology, it is now possible to further elucidate their molecular properties and cellular fate changes. By discovering the fundamental molecular characteristics of these cells, it may be possible to harness their functional characteristics for skeletal growth and regeneration. Here, we discuss our current understanding of the molecular signatures defining growth plate chondrocytes.

scholarly journals Thyroid Hormone Regulates Heparan Sulfate Proteoglycan Expression in the Growth Plate

Endocrinology ◽  
2006 ◽  
Vol 147 (1) ◽  
pp. 295-305 ◽  
Author(s):  
J. H. D. Bassett ◽  
R. Swinhoe ◽  
O. Chassande ◽  
J. Samarut ◽  
G. R. Williams
Keyword(s):  
Thyroid Hormone ◽  
Heparan Sulfate ◽  
Growth Plate ◽  
Hedgehog Signaling ◽  
Hormone Receptors ◽  
Core Protein ◽  
Skeletal Development ◽  
Indian Hedgehog ◽  
Fgf Receptor ◽  
Modification Enzyme

Thyroid hormone is essential for normal skeletal development. Hypothyroidism is associated with growth arrest, failure of chondrocyte differentiation, and abnormal matrix synthesis. Thyroid hormone modulates the Indian hedgehog/PTHrP feedback loop and regulates fibroblast growth factor (FGF)/FGF receptor signaling. Because heparan sulfate (HS) proteoglycans (Prgs) (HSPGs) are absolutely required by these signaling pathways, we have investigated whether thyroid status affects HSPG expression within the growth plate. Tibial growth plate sections were obtained from 12-wk-old rats rendered euthyroid, thyrotoxic, or hypothyroid at 6 wk of age, 14-d-old congenitally hypothyroid Pax8-null mice, and TRα/TRβ double-null mice lacking all thyroid hormone receptors. HS and chondroitin sulfate Prg expression was determined by immunohistochemistry using three monoclonal antibodies. There was increased HS staining in growth plates from hypothyroid animals predominantly within the extracellular matrix of reserve and proliferative zones. Cellular HS staining was also increased particularly in prehypertrophic chondrocytes. T3 regulation of HSPG core protein and HS synthetic and modification enzyme expression was studied in ATDC5 cells using semiquantitative RT-PCR. Thyroid hormone negatively regulated expression of the core protein Gpc6, the polymerase Ext1, and the modification enzyme Hs6st2. These studies demonstrate that the expression and distribution of growth plate Prgs are regulated by thyroid hormone, and the regulation of HSPG expression provides an important additional link between FGF and Indian hedgehog signaling and T3. These novel observations suggest that the cartilage matrix and especially HSPGs are critical mediators of the skeletal response to thyroid hormone.

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.

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