scholarly journals The Role of Hedgehog Signaling in Adult Lung Regeneration and Maintenance

2019 ◽  
Vol 7 (3) ◽  
pp. 14 ◽  
Author(s):  
Chaoqun Wang ◽  
Monica Cassandras ◽  
Tien Peng
Keyword(s):  
Cell Fate ◽  
Hedgehog Signaling ◽  
Structural Integrity ◽  
Current Knowledge ◽  
Cell Fates ◽  
Adult Lung ◽  
Hh Signaling ◽  
Key Aspects ◽  
And Behavior ◽  
Lung Regeneration

As a secreted morphogen, Sonic Hedgehog (SHH) determines differential cell fates, behaviors, and functions by forming a gradient of Hedgehog (Hh) activation along an axis of Hh-receptive cells during development. Despite clearly delineated roles for Hh during organ morphogenesis, whether Hh continues to regulate cell fate and behavior in the same fashion in adult organs is less understood. Adult organs, particularly barrier organs interfacing with the ambient environment, are exposed to insults that require renewal of cellular populations to maintain structural integrity. Understanding key aspects of Hh’s ability to generate an organ could translate into conceptual understanding of Hh’s ability to maintain organ homeostasis and stimulate regeneration. In this review, we will summarize the current knowledge about Hh signaling in regulating adult lung regeneration and maintenance, and discuss how alteration of Hh signaling contributes to adult lung diseases.

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

2019 ◽  
Vol 20 (12) ◽  
pp. 3076 ◽  
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.

Hedgehog Signaling Is Dispensable for Adult Murine Hematopoiesis and Leukemogenesis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1391-1391
Author(s):  
Inga Hofmann Zhang ◽  
Elizabeth H. Stover ◽  
Dana E. Cullen ◽  
Junhao Mao ◽  
Kelly J. Morgan ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Cell Fate ◽  
Intracellular Signaling ◽  
Hedgehog Signaling ◽  
Unexpected Finding ◽  
Hematopoietic Stem ◽  
Developmental Abnormalities ◽  
Hh Signaling ◽  
Pharmacologic Inhibition

Abstract Hedgehog (Hh) pathway proteins are a highly conserved family of intracellular signaling molecules that are critical for the development of multiple organs and tissues, and play a role in cell fate determination of self-renewing tissues in the adult. Mutations that impair Hh signaling have been associated with developmental abnormalities, and recent studies indicate that Hh plays an important role in hemangioblast formation and in adult hematopoiesis, as well as in the differentiation and proliferation of hematopoietic stem cells (HSC) and progenitor cells. We used a genetic and pharmacologic approach to define the role of the Hh pathway in adult hematopoiesis and leukemogenesis. We report the unexpected finding that loss of Hh signaling through conditional deletion of Smoothened (Smo) in the adult hematopoietic compartment has no effect on adult hematopoiesis, including peripheral blood count, number or cell cycle status of stem and progenitor cells, hematopoietic colony forming potential, long-term repopulating activity in competitive repopulation assays, or stress-response to serial 5-fluorouracil treatment. In support of these observations based on genetic inactivation of the pathway, we observed that pharmacologic inhibition of Hh signaling with a potent and highly selective small molecule antagonist of Smo has no apparent effect on hematopoiesis in the mouse in vivo. In addition, we observed that Hh signaling is not required for the development of MLL-AF9 mediated leukemia. Taken together, these data indicate that Hh signaling is dispensable for normal hematopoietic development and leukemogenesis, and that pharmacologic inhibition of Hh signaling, as a therapeutic strategy in treatment of solid tumors with constitutive Hh pathway activation is not likely to be associated with unmanageable hematopoietic toxicity.

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

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.

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.

Wingless, decapentaplegic and EGF receptor signaling pathways interact to specify dorso-ventral pattern in the adult abdomen of Drosophila

Development ◽  
1999 ◽  
Vol 126 (16) ◽  
pp. 3495-3507 ◽  
Author(s):  
A. Kopp ◽  
R.K. Blackman ◽  
I. Duncan
Keyword(s):  
Cell Fate ◽  
Transcriptional Repression ◽  
Hedgehog Signaling ◽  
Egf Receptor ◽  
Pupal Stage ◽  
Cell Fates ◽  
Medial Region ◽  
Dorsal Midline ◽  
Anterior Compartment ◽  
Adult Abdomen

Adult abdominal segments of Drosophila are subdivided along the dorso-ventral axis into a dorsal tergite, a ventral sternite and ventro-lateral pleural cuticle. We report that this pattern is largely specified during the pupal stage by Wingless (Wg), Decapentaplegic (Dpp) and Drosophila EGF Receptor (DER) signaling. Expression of wg and dpp is activated at the posterior edge of the anterior compartment by Hedgehog signaling. Within this region, wg and dpp are expressed in domains that are mutually exclusive along the dorso-ventral axis: wg is expressed in the sternite and medio-lateral tergite, whereas dpp expression is confined to the pleura and the dorsal midline. Neither gene is expressed in the lateral tergite. Shirras and Couso (1996, Dev. Biol. 175, 24–36) have shown that tergite and sternite cell fates are specified by Wg signaling. We find that DER acts synergistically with Wg to promote tergite and sternite identities, and that Wg and DER activities are opposed by Dpp signaling, which promotes pleural identity. Wg and Dpp interact antagonistically at two levels. First, their expression is confined to complementary domains by mutual transcriptional repression. Second, Wg and Dpp compete directly with one another by exerting opposite effects on cell fate. DER signaling does not affect the expression of wg or dpp, indicating that it interacts with Wg and Dpp at the level of cell fate determination. Within the tergite, the requirements for Wg and DER function are roughly complementary: Wg is required mainly in the medial region, whereas DER is most important laterally. Finally, we show that Dpp signaling at the dorsal midline controls dorso-ventral patterning within the tergite by promoting pigmentation in the medial region.

scholarly journals Drosophila Notch receptor activity suppresses Hairless function during adult external sensory organ development.

Genetics ◽  
1995 ◽  
Vol 141 (4) ◽  
pp. 1491-1505
Author(s):  
D F Lyman ◽  
B Yedvobnick
Keyword(s):  
Cell Fate ◽  
Daughter Cell ◽  
Notch Receptor ◽  
Sensory Organ ◽  
Cell Fates ◽  
Gain Of Function ◽  
Over Expression ◽  
Cell Fate Decisions ◽  
Synergistic Enhancement ◽  
Conditional Expression

Abstract The neurogenic Notch locus of Drosophila encodes a receptor necessary for cell fate decisions within equivalence groups, such as proneural clusters. Specification of alternate fates within clusters results from inhibitory communication among cells having comparable neural fate potential. Genetically, Hairless (H) acts as an antagonist of most neurogenic genes and may insulate neural precursor cells from inhibition. H function is required for commitment to the bristle sensory organ precursor (SOP) cell fate and for daughter cell fates. Using Notch gain-of-function alleles and conditional expression of an activated Notch transgene, we show that enhanced signaling produces H-like loss-of-function phenotypes by suppressing bristle SOP cell specification or by causing an H-like transformation of sensillum daughter cell fates. Furthermore, adults carrying Notch gain of function and H alleles exhibit synergistic enhancement of mutant phenotypes. Over-expression of an H+ transgene product suppressed virtually all phenotypes generated by Notch gain-of-function genotypes. Phenotypes resulting from over-expression of the H+ transgene were blocked by the Notch gain-of-function products, indicating a balance between Notch and H activity. The results suggest that H insulates SOP cells from inhibition and indicate that H activity is suppressed by Notch signaling.

scholarly journals Lipid Transporters Beam Signals from Cell Membranes

Membranes ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 562
Author(s):  
Miliça Ristovski ◽  
Danny Farhat ◽  
Shelly Ellaine M. Bancud ◽  
Jyh-Yeuan Lee
Keyword(s):  
Membrane Proteins ◽  
Lipid Bilayers ◽  
Lipid Composition ◽  
Structural Integrity ◽  
Current Knowledge ◽  
Integral Membrane Proteins ◽  
Cellular Membranes ◽  
Cytoplasmic Proteins ◽  
Lipid Transporters

Lipid composition in cellular membranes plays an important role in maintaining the structural integrity of cells and in regulating cellular signaling that controls functions of both membrane-anchored and cytoplasmic proteins. ATP-dependent ABC and P4-ATPase lipid transporters, two integral membrane proteins, are known to contribute to lipid translocation across the lipid bilayers on the cellular membranes. In this review, we will highlight current knowledge about the role of cholesterol and phospholipids of cellular membranes in regulating cell signaling and how lipid transporters participate this process.

scholarly journals Neuronal Cytoskeleton in Intellectual Disability: From Systems Biology and Modeling to Therapeutic Opportunities

2021 ◽  
Vol 22 (11) ◽  
pp. 6167
Author(s):  
Carla Liaci ◽  
Mattia Camera ◽  
Giovanni Caslini ◽  
Simona Rando ◽  
Salvatore Contino ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Systems Biology ◽  
Rho Gtpases ◽  
Current Knowledge ◽  
Pathological Condition ◽  
Hierarchical Arrangement ◽  
Worldwide Population ◽  
Id Genes ◽  
Effective Network ◽  
And Behavior

Intellectual disability (ID) is a pathological condition characterized by limited intellectual functioning and adaptive behaviors. It affects 1–3% of the worldwide population, and no pharmacological therapies are currently available. More than 1000 genes have been found mutated in ID patients pointing out that, despite the common phenotype, the genetic bases are highly heterogeneous and apparently unrelated. Bibliomic analysis reveals that ID genes converge onto a few biological modules, including cytoskeleton dynamics, whose regulation depends on Rho GTPases transduction. Genetic variants exert their effects at different levels in a hierarchical arrangement, starting from the molecular level and moving toward higher levels of organization, i.e., cell compartment and functions, circuits, cognition, and behavior. Thus, cytoskeleton alterations that have an impact on cell processes such as neuronal migration, neuritogenesis, and synaptic plasticity rebound on the overall establishment of an effective network and consequently on the cognitive phenotype. Systems biology (SB) approaches are more focused on the overall interconnected network rather than on individual genes, thus encouraging the design of therapies that aim to correct common dysregulated biological processes. This review summarizes current knowledge about cytoskeleton control in neurons and its relevance for the ID pathogenesis, exploiting in silico modeling and translating the implications of those findings into biomedical research.

scholarly journals Histone Acetyltransferases and Stem Cell Identity

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2407
Author(s):  
Ruicen He ◽  
Arthur Dantas ◽  
Karl Riabowol
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Epigenetic Modification ◽  
Cell Types ◽  
Histone Acetyltransferases ◽  
Specific Cell ◽  
Cell Fates ◽  
Cell Identity ◽  
Hematopoietic Stem

Acetylation of histones is a key epigenetic modification involved in transcriptional regulation. The addition of acetyl groups to histone tails generally reduces histone-DNA interactions in the nucleosome leading to increased accessibility for transcription factors and core transcriptional machinery to bind their target sequences. There are approximately 30 histone acetyltransferases and their corresponding complexes, each of which affect the expression of a subset of genes. Because cell identity is determined by gene expression profile, it is unsurprising that the HATs responsible for inducing expression of these genes play a crucial role in determining cell fate. Here, we explore the role of HATs in the maintenance and differentiation of various stem cell types. Several HAT complexes have been characterized to play an important role in activating genes that allow stem cells to self-renew. Knockdown or loss of their activity leads to reduced expression and or differentiation while particular HATs drive differentiation towards specific cell fates. In this study we review functions of the HAT complexes active in pluripotent stem cells, hematopoietic stem cells, muscle satellite cells, mesenchymal stem cells, neural stem cells, and cancer stem cells.

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