Hedgehog signaling controls mouth opening in the amphioxus

Abstract Introduction The left-sided position of the mouth in amphioxus larvae has fascinated researchers for a long time. Despite the fundamental importance of mouth development in the amphioxus, the molecular regulation of its development is almost unknown. In our previous study, we showed that Hh mutation in the amphioxus leads to no mouth opening, indicating a requirement of Hh signaling for amphioxus mouth formation. Nevertheless, since the Hh mutant also exhibits defects in early left-right (LR) patterning, it remains currently unknown whether the loss of mouth opening is affected directly by Hh deficiency or a secondary effect of its influence on LR establishment. Results We demonstrated that knockout of the Smo gene, another key component of the Hh signaling pathway, in the amphioxus resulted in the absence of mouth opening, but caused no effects on LR asymmetry development. Upregulation of Hh signaling led to a dramatic increase in mouth size. The inability of Smo mutation to affect LR development is due to Smo’s high maternal expression in amphioxus eggs and cleavage-stage embryos. In Smo mutants, Pou4 and Pax2/5/8 expression at the primordial oral site is not altered before mouth opening. Conclusions Based on these results and our previous study, we conclude that Hh signal is necessary for amphioxus mouth formation and that the Hh-mediated regulation of mouth development is specific to the mouth. Our data suggest that Hh signaling regulates mouth formation in the amphioxus in a similar way as that in vertebrates, indicating the conserved role of Hh signaling in mouth formation.

Download Full-text

Role of knot (kn) in Wing Patterning in Drosophila

Genetics ◽

10.1093/genetics/147.3.1203 ◽

1997 ◽

Vol 147 (3) ◽

pp. 1203-1212 ◽

Cited By ~ 1

Author(s):

Katerina Nestoras ◽

Helena Lee ◽

Jym Mohler

Keyword(s):

Hedgehog Signaling ◽

Imaginal Disc ◽

Hedgehog Signaling Pathway ◽

Posterior Compartment ◽

Drosophila Wing ◽

Compartment Boundary ◽

Hh Signaling ◽

Embryonic Segmentation ◽

Anterior Posterior

We have undertaken a genetic analysis of new strong alleles of knot (kn). The original kn1 mutation causes an alteration of wing patterning similar to that associated with mutations of fused (fu), an apparent fusion of veins 3 and 4 in the wing. However, unlike fu, strong kn mutations do not affect embryonic segmentation and indicate that kn is not a component of a general Hh (Hedgehog)-signaling pathway. Instead we find that kn has a specific role in those cells of the wing imaginal disc that are subject to ptc-mediated Hh-signaling. Our results suggest a model for patterning the medial portion of the Drosophila wing, whereby the separation of veins 3 and 4 is maintained by kn activation in the intervening region in response to Hh-signaling across the adjacent anterior-posterior compartment boundary.

Download Full-text

Role of the Hedgehog Signaling Pathway in Regulating the Behavior of Germline Stem Cells

Stem Cells International ◽

10.1155/2017/5714608 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Shiqin Li ◽

Meng Wang ◽

Yanghui Chen ◽

Wei Wang ◽

Junying Wu ◽

...

Keyword(s):

Stem Cells ◽

Signaling Pathway ◽

Hedgehog Signaling ◽

Adult Stem Cells ◽

Reproductive Function ◽

Future Research ◽

Germline Stem Cells ◽

Proliferation And Differentiation ◽

Hh Signaling

Germline stem cells (GSCs) are adult stem cells that are responsible for the production of gametes and include spermatogonial stem cells (SSCs) and ovarian germline stem cells (OGSCs). GSCs are located in a specialized microenvironment in the gonads called the niche. Many recent studies have demonstrated that multiple signals in the niche jointly regulate the proliferation and differentiation of GSCs, which is of significance for reproductive function. Previous studies have demonstrated that the hedgehog (Hh) signaling pathway participates in the proliferation and differentiation of various stem cells, including GSCs in Drosophila and male mammals. Furthermore, the discovery of mammalian OGSCs challenged the traditional opinion that the number of primary follicles is fixed in postnatal mammals, which is of significance for the reproductive ability of female mammals and the treatment of diseases related to germ cells. Meanwhile, it still remains to be determined whether the Hh signaling pathway participates in the regulation of the behavior of OGSCs. Herein, we review the current research on the role of the Hh signaling pathway in mediating the behavior of GSCs. In addition, some suggestions for future research are proposed.

Download Full-text

Role of Hedgehog Signaling in Vasculature Development, Differentiation, and Maintenance

International Journal of Molecular Sciences ◽

10.3390/ijms20123076 ◽

2019 ◽

Vol 20 (12) ◽

pp. 3076 ◽

Cited By ~ 13

Author(s):

Candice Chapouly ◽

Sarah Guimbal ◽

Pierre-Louis Hollier ◽

Marie-Ange Renault

Keyword(s):

Hedgehog Signaling ◽

Current Knowledge ◽

Vascular Biology ◽

Cerebrovascular Diseases ◽

Future Research ◽

Cellular Mechanisms ◽

Vascular Integrity ◽

Hh Signaling ◽

Vessel Integrity

The role of Hedgehog (Hh) signaling in vascular biology has first been highlighted in embryos by Pepicelli et al. in 1998 and Rowitch et al. in 1999. Since then, the proangiogenic role of the Hh ligands has been confirmed in adults, especially under pathologic conditions. More recently, the Hh signaling has been proposed to improve vascular integrity especially at the blood–brain barrier (BBB). However, molecular and cellular mechanisms underlying the role of the Hh signaling in vascular biology remain poorly understood and conflicting results have been reported. As a matter of fact, in several settings, it is currently not clear whether Hh ligands promote vessel integrity and quiescence or destabilize vessels to promote angiogenesis. The present review relates the current knowledge regarding the role of the Hh signaling in vasculature development, maturation and maintenance, discusses the underlying proposed mechanisms and highlights controversial data which may serve as a guideline for future research. Most importantly, fully understanding such mechanisms is critical for the development of safe and efficient therapies to target the Hh signaling in both cancer and cardiovascular/cerebrovascular diseases.

Download Full-text

The Hedgehog Regulated Transcription Factor and Tumor Suppressor, Gli3, Regulates Hematopoietic Stem Cell Number, Self-Renewal and Differentiation

Blood ◽

10.1182/blood.v126.23.2381.2381 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2381-2381

Author(s):

Parvesh Chaudhry ◽

Mohan Singh ◽

Amy R McManus ◽

Aparna Jorapur ◽

Stephen James Capone ◽

...

Keyword(s):

Transcription Factor ◽

Tumor Suppressor ◽

Hedgehog Signaling ◽

Fine Tuning ◽

Myeloid Differentiation ◽

Self Renewal ◽

Hematopoietic System ◽

Hh Signaling

Abstract The Hedgehog (Hh) signaling pathway plays a critical role in embryonic development and adult tissue homeostasis and has emerged as an important therapeutic target in many cancers, including leukemia and myeloproliferative diseases. Our mechanistic understanding of Hh pathway signaling and regulation comes primarily from developmental studies in neural and limb development. Studies of Hedgehog signaling in the hematopoietic system have produced contradictory results, and no clear consensus regarding Hh signaling in normal hematopoiesis is available to inform the role of Hedgehog signaling in hematologic malignancies. In our work we have focused on understanding the downstream effectors of Hedgehog signaling, the Gli transcription factors. The three Gli proteins, Gli1, Gli2 and Gli3 have both transcriptional activator and repressor functions, which allow for regulation and fine-tuning of Hedgehog pathway output. Previous studies from our group have revealed that Gli1null HSCs had no defects in self-renewal, however myeloid differentiation and stress hematopoiesis were severely impaired (Merchant, et al., Blood 2010). In normal tissues, Hh pathway activation via Ptch/Smo causes an increase in the downstream activating transcription factor GLI1 and a decrease in the transcriptional repressor Gli3R. Our recent studies demonstrated that GLI3R has a tumor suppressor role in human acute myeloid leukemia by directly repressing AKT expression (Chaudhry et al., AACR Annual Meeting 2015). To date nothing is known about the role of Gli3 in normal hematopoiesis. In the present study, we crossed Vav-Cre transgenic mice to Gli3fl/fl mice to generate mice with a conditional loss of Gli3 (Gli3null) in the hematopoietic system. HSC self-renewal was analyzed by serial transplant. In comparison to HSCs from Gli3 wild type (Gli3WT) mice bone marrow (BM), HSCs from Gli3null BM showed decreased long-term engraftment and self-renewal. In addition, quantification of long-term HSC (LT-HSC, CD34neg Flt3neg KSL), short-term HSC (ST-HSC, CD34+ Flt3neg KSL), and multi-potent progenitor (MPP, CD34+ Flt3+ KSL) revealed that the frequency of LT-HSCs in Gli3null BM (0.004-0.007%) was lower compared to Gli3 WT BM (0.008-0.02%). In mice transplanted with Gli3null BM, myeloid expansion was observed with a block in T and B cell lineage differentiation. Analysis of the c-Kit+ Sca1neg Linneg (KL) myeloid progenitor compartment revealed a two-fold increase in the FcRγhigh CD34+ KL granulocyte-monocyte progenitors (GMPs) in Gli3null BM, suggesting an expansion of granulocytic compartment. Since Gli3R is a key negative regulator of Gli1, these are consistent with decrease in GMP and myeloid differentiation previously seen in Gli1null mice. In summary, our studies reveal a previously unknown function for Gli3 in regulating HSCs and myeloid differentiation, and help to elucidate the complex regulation of Hh signaling in the hematopoietic system. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Hedgehog Signaling in Colorectal Cancer: All in the Stroma?

International Journal of Molecular Sciences ◽

10.3390/ijms22031025 ◽

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.

Download Full-text

Roles of the Hedgehog Signaling Pathway in Skin Development, Homeostasis and Cancer

10.20944/preprints201711.0096.v1 ◽

2017 ◽

Author(s):

Yoshinori Abe ◽

Nobuyuki Tanaka

Keyword(s):

Basal Cell Carcinoma ◽

Cell Carcinoma ◽

Signaling Pathway ◽

Basal Cell ◽

Hedgehog Signaling ◽

Current Knowledge ◽

Skin Development ◽

Morphogenetic Protein ◽

Hh Signaling

The epidermis is the outermost layer of skin and provides a protective barrier against environmental insults. It is a rapidly renewing tissue undergoing constant regeneration, maintained by several types of stem cells. Hedgehog (HH) ligands activate one of the fundamental signaling pathways that contribute to epidermal development, homeostasis and repair. The HH pathway interacts with other signal transduction pathways such as those activated by Wnt and bone morphogenetic protein. Furthermore, aberrant activation of HH signaling is associated with various tumors, including basal cell carcinoma. Therefore, an understanding of the regulatory mechanisms of the HH signaling pathway is important to elucidate fundamental mechanisms underlying both organogenesis and carcinogenesis. In this review, we discuss the role of the HH signaling pathway in skin development, homeostasis and basal cell carcinoma formation, providing an update of current knowledge in this field.

Download Full-text

Role of Hedgehog Signaling in Breast Cancer: Pathogenesis and Therapeutics

Cells ◽

10.3390/cells8040375 ◽

2019 ◽

Vol 8 (4) ◽

pp. 375 ◽

Cited By ~ 21

Author(s):

Natalia Riobo-Del Galdo ◽

Ángela Lara Montero ◽

Eva Wertheimer

Keyword(s):

Breast Cancer ◽

Hedgehog Signaling ◽

Treatment Guidelines ◽

Breast Development ◽

Cell Renewal ◽

Stem Cell Renewal ◽

Cancer Pathogenesis ◽

Tumorigenesis And Progression ◽

Hh Signaling

Breast cancer (BC) is the leading cause of cancer-related mortality in women, only followed by lung cancer. Given the importance of BC in public health, it is essential to identify biomarkers to predict prognosis, predetermine drug resistance and provide treatment guidelines that include personalized targeted therapies. The Hedgehog (Hh) signaling pathway plays an essential role in embryonic development, tissue regeneration, and stem cell renewal. Several lines of evidence endorse the important role of canonical and non-canonical Hh signaling in BC. In this comprehensive review we discuss the role of Hh signaling in breast development and homeostasis and its contribution to tumorigenesis and progression of different subtypes of BC. We also examine the efficacy of agents targeting different components of the Hh pathway both in preclinical models and in clinical trials. The contribution of the Hh pathway in BC tumorigenesis and progression, its prognostic role, and its value as a therapeutic target vary according to the molecular, clinical, and histopathological characteristics of the BC patients. The evidence presented here highlights the relevance of the Hh signaling in BC, and suggest that this pathway is key for BC progression and metastasis.

Download Full-text

The Hedgehog Signaling Pathway in Ischemic Tissues

International Journal of Molecular Sciences ◽

10.3390/ijms20215270 ◽

2019 ◽

Vol 20 (21) ◽

pp. 5270 ◽

Cited By ~ 2

Author(s):

Igor Giarretta ◽

Eleonora Gaetani ◽

Margherita Bigossi ◽

Paolo Tondi ◽

Takayuki Asahara ◽

...

Keyword(s):

Signaling Pathway ◽

Tissue Regeneration ◽

Hedgehog Signaling ◽

Potential Role ◽

Hedgehog Signaling Pathway ◽

Pathological Conditions ◽

Ischemic Tissue ◽

Hh Signaling ◽

The Brain

Hedgehog (Hh) proteins are prototypical morphogens known to regulate epithelial/mesenchymal interactions during embryonic development. In addition to its pivotal role in embryogenesis, the Hh signaling pathway may be recapitulated in post-natal life in a number of physiological and pathological conditions, including ischemia. This review highlights the involvement of Hh signaling in ischemic tissue regeneration and angiogenesis, with particular attention to the heart, the brain, and the skeletal muscle. Updated information on the potential role of the Hh pathway as a therapeutic target in the ischemic condition is also presented.

Download Full-text

Defining the Role of GLI/Hedgehog Signaling in Chemoresistance: Implications in Therapeutic Approaches

Cancers ◽

10.3390/cancers13194746 ◽

2021 ◽

Vol 13 (19) ◽

pp. 4746

Author(s):

Jian Yi Chai ◽

Vaisnevee Sugumar ◽

Ahmed F. Alshanon ◽

Won Fen Wong ◽

Shin Yee Fung ◽

...

Keyword(s):

Signaling Pathway ◽

Cancer Progression ◽

Hedgehog Signaling ◽

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Treatment Strategies ◽

Cancer Treatments ◽

Mesenchymal Transition ◽

Hh Signaling

Insight into cancer signaling pathways is vital in the development of new cancer treatments to improve treatment efficacy. A relatively new but essential developmental signaling pathway, namely Hedgehog (Hh), has recently emerged as a major mediator of cancer progression and chemoresistance. The evolutionary conserved Hh signaling pathway requires an in-depth understanding of the paradigm of Hh signaling transduction, which is fundamental to provide the necessary means for the design of novel tools for treating cancer related to aberrant Hh signaling. This review will focus substantially on the canonical Hh signaling and the treatment strategies employed in different studies, with special emphasis on the molecular mechanisms and combination treatment in regard to Hh inhibitors and chemotherapeutics. We discuss our views based on Hh signaling’s role in regulating DNA repair machinery, autophagy, tumor microenvironment, drug inactivation, transporters, epithelial-to-mesenchymal transition, and cancer stem cells to promote chemoresistance. The understanding of this Achilles’ Heel in cancer may improve the therapeutic outcome for cancer therapy.

Download Full-text