Hedgehog signaling is required for primary motoneuron induction in zebrafish

Development ◽  
2001 ◽  
Vol 128 (18) ◽  
pp. 3485-3495 ◽  
Author(s):  
Katharine E. Lewis ◽  
Judith S. Eisen
Keyword(s):  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
The Other ◽  
Zebrafish Embryos ◽  
Normal Numbers ◽  
Hh Signaling ◽  
Primary Motoneuron

Sonic hedgehog (Shh) is crucial for motoneuron development in chick and mouse. However, zebrafish embryos homozygous for a deletion of the shh locus have normal numbers of motoneurons, raising the possibility that zebrafish motoneurons may be specified differently. Unlike other vertebrates, zebrafish express three hh genes in the embryonic midline: shh, echidna hedgehog (ehh) and tiggywinkle hedgehog (twhh). Therefore, it is possible that Twhh and Ehh are sufficient for motoneuron formation in the absence of Shh. To test this hypothesis we have eliminated, or severely reduced, all three Hh signals using mutations that directly or indirectly reduce Hh signaling and antisense morpholinos. Our analysis shows that Hh signals are required for zebrafish motoneuron induction. However, each of the three zebrafish Hhs is individually dispensable for motoneuron development because the other two can compensate for its loss. Our results also suggest that Twhh and Shh are more important for motoneuron development than Ehh.

scholarly journals Native V. Californicum Alkaloid Combinations Induce Differential Inhibition of Sonic Hedgehog Signaling

2018 ◽  
Author(s):  
Matthew W. Turner ◽  
Roberto Cruz ◽  
Jordan Elwell ◽  
John French ◽  
Jared Mattos ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Plant Part ◽  
Differential Inhibition ◽  
Sonic Hedgehog Signaling ◽  
Alkaloid Composition ◽  
Hh Signaling ◽  
Inhibitory Potential ◽  
Pathway Inhibition

Veratrum californicum is a rich source of steroidal alkaloids such as cyclopamine, a known inhibitor of the Hedgehog (Hh) signaling pathway. Here we provide a detailed analysis of the alkaloid composition of V. californicum by plant part through quantitative analysis of cyclopamine, veratramine, muldamine and isorubijervine in the leaf, stem and root/rhizome of the plant. To determine if additional alkaloids in the extracts contribute to Hh signaling inhibition, we replicated the concentrations of these alkaloids observed in extracts using commercially available standards and compared the inhibitory potential of the extracts to alkaloid standard mixtures using Shh-Light II cells. Alkaloid combinations enhanced Hh signaling pathway antagonism compared to cyclopamine alone, and significant differences were observed in the Hh pathway inhibition between the stem and root/rhizome extracts and their corresponding alkaloid standard mixtures, indicating that additional alkaloids present in these extracts contribute to Hh signaling inhibition.

Scl and Notch Act Downstream of Hedgehog Signaling to Promote Embryonic Hematopoiesis From Endothelial Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1283-1283
Author(s):  
Peter G Kim ◽  
Colleen E Albacker ◽  
Il-ho Jang ◽  
Garrett C Heffner ◽  
Yoowon Lim ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Signaling Pathways ◽  
Board Of Directors ◽  
Hedgehog Signaling ◽  
Embryonic Stem ◽  
Zebrafish Embryos ◽  
Hematopoietic Tissue ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Hh Signaling

Abstract Abstract 1283 Adult hematopoietic cells transition through a hemogenic endothelial (HE) intermediate during development, but the signaling pathways modulating this transition are incompletely characterized. Although the Hedgehog (Hh) pathway is hypothesized to play a role in blood and endothelial cell formation, early embryonic lethality of mice lacking Hedgehog signaling precludes such analysis. To determine a role for Hh signaling in HE patterning, we assessed the effect of altered Hh signaling in differentiating mouse embryonic stem cells (mESCs), cultured embryonic day 9.5 mouse embryos, and developing zebrafish embryos. In differentiating mESCs, addition of Indian Hh ligand (IHH) increased the number of CD41+c-Kit+ hematopoietic progenitors, whereas chemical inhibition of Hh signaling led to a decrease without affecting primitive-streak mesoderm gene expression. In the setting of Hh inhibition, Notch induction rescued hemogenic VE-cadherin+ cells, demonstrating that Notch expands HE. Scl/Tal1 (stem cell leukemia/T-cell associated leukemia 1) induction rescued VE-cadherin+CD41+ cells, demonstrating that Scl/Tal1 converts endothelial cells to hematopoietic tissue. Similar experiments using cultured mouse yolk sacs demonstrated that signaling pathways are conserved in vivo. Moreover, VE-cadherin+ cells isolated from the mouse yolk sac or paraaortic splanchnopleura, when virally transduced with Notch signaling or Scl, had increased hematopoietic colony-forming activity. Finally, ectopic Notch or Scl induction in zebrafish embryos rescued the expression of the prototypical hemogenic endothelium marker Runx1 in the absence of Hh signalling. Together, our results reveal that the Hh-Notch-Scl axis promotes embryonic hematopoiesis through endothelial-to-hematopoietic transition. Disclosures: Zon: Fate Therapeutics: Consultancy; Stemgent: Consultancy. Daley:iPierian, Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Epizyme, Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Verastem, Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Solasia, KK: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; MPM Capital, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees.

scholarly journals p63 sustains self-renewal of mammary cancer stem cells through regulation of Sonic Hedgehog signaling

2015 ◽  
Vol 112 (11) ◽  
pp. 3499-3504 ◽  
Author(s):  
Elisa Maria Memmi ◽  
Anna Giulia Sanarico ◽  
Arianna Giacobbe ◽  
Angelo Peschiaroli ◽  
Valentina Frezza ◽  
...  
Keyword(s):  
Stem Cell ◽  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Breast Tumorigenesis ◽  
Sonic Hedgehog Signaling ◽  
Self Renewal ◽  
Genes Encoding ◽  
Hh Signaling

The predominant p63 isoform, ΔNp63, is a master regulator of normal epithelial stem cell (SC) maintenance. However, in vivo evidence of the regulation of cancer stem cell (CSC) properties by p63 is still limited. Here, we exploit the transgenic MMTV-ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2) mouse model of carcinogenesis to dissect the role of p63 in the regulation of mammary CSC self-renewal and breast tumorigenesis. ErbB2 tumor cells enriched for SC-like properties display increased levels of ΔNp63 expression compared with normal mammary progenitors. Down-regulation of p63 in ErbB2 mammospheres markedly restricts self-renewal and expansion of CSCs, and this action is fully independent of p53. Furthermore, transplantation of ErbB2 progenitors expressing shRNAs against p63 into the mammary fat pads of syngeneic mice delays tumor growth in vivo. p63 knockdown in ErbB2 progenitors diminishes the expression of genes encoding components of the Sonic Hedgehog (Hh) signaling pathway, a driver of mammary SC self-renewal. Remarkably, p63 regulates the expression of Sonic Hedgehog (Shh), GLI family zinc finger 2 (Gli2), and Patched1 (Ptch1) genes by directly binding to their gene regulatory regions, and eventually contributes to pathway activation. Collectively, these studies highlight the importance of p63 in maintaining the self-renewal potential of mammary CSCs via a positive modulation of the Hh signaling pathway.

scholarly journals Selective Targeting of the Hedgehog Signaling Pathway by PBM Nanoparticles in Docetaxel-Resistant Prostate Cancer

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1976
Author(s):  
Santosh Kumar Singh ◽  
Jennifer B. Gordetsky ◽  
Sejong Bae ◽  
Edward P. Acosta ◽  
James W. Lillard ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Resistant Disease ◽  
Natural Polysaccharide ◽  
Selective Targeting ◽  
Hh Signaling ◽  
Gli 1 ◽  
Specific Membrane

An abnormality in hedgehog (Hh) signaling has been implicated in the progression of prostate cancer (PCa) to a more aggressive and therapy-resistant disease. Our assessments of human PCa tissues have shown an overexpression of the Hh pathway molecules, glioma-associated oncogene homolog 1 (GLI-1), and sonic hedgehog (SHH). The effect of the natural compound thymoquinone (TQ) in controlling the expression of Hh signaling molecules in PCa was investigated in this study. We generated planetary ball-milled nanoparticles (PBM-NPs) made with a natural polysaccharide, containing TQ, and coated with an RNA aptamer, A10, which binds to prostate-specific membrane antigen (PSMA). We prepared docetaxel-resistant C4-2B-R and LNCaP-R cells with a high expression of Hh, showing the integration of drug resistance and Hh signaling. Compared to free TQ, A10-TQ-PBM-NPs were more effective in controlling the Hh pathway. Our findings reveal an effective treatment strategy to inhibit the Hh signaling pathway, thereby suppressing PCa progression.

scholarly journals Native V. californicum Alkaloid Combinations Induce Differential Inhibition of Sonic Hedgehog Signaling

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2222 ◽  
Author(s):  
Matthew Turner ◽  
Roberto Cruz ◽  
Jordan Elwell ◽  
John French ◽  
Jared Mattos ◽  
...  
Keyword(s):  
Quantitative Analysis ◽  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Plant Part ◽  
Differential Inhibition ◽  
Sonic Hedgehog Signaling ◽  
Alkaloid Composition ◽  
Hh Signaling ◽  
Pathway Inhibition

Veratrum californicum is a rich source of steroidal alkaloids such as cyclopamine, a known inhibitor of the Hedgehog (Hh) signaling pathway. Here we provide a detailed analysis of the alkaloid composition of V. californicum by plant part through quantitative analysis of cyclopamine, veratramine, muldamine and isorubijervine in the leaf, stem and root/rhizome of the plant. To determine whether additional alkaloids in the extracts contribute to Hh signaling inhibition, the concentrations of these four alkaloids present in extracts were replicated using commercially available standards, followed by comparison of extracts to alkaloid standard mixtures for inhibition of Hh signaling using Shh-Light II cells. Alkaloid combinations enhanced Hh signaling pathway antagonism compared to cyclopamine alone, and significant differences were observed in the Hh pathway inhibition between the stem and root/rhizome extracts and their corresponding alkaloid standard mixtures, indicating that additional alkaloids present in these extracts are capable of inhibiting Hh signaling.

The Adventures of Sonic Hedgehog in Development and Repair. I. Hedgehog signaling in gastrointestinal development and disease

2008 ◽  
Vol 294 (2) ◽  
pp. G363-G367 ◽  
Author(s):  
Caroline A. Parkin ◽  
Philip W. Ingham
Keyword(s):  
Signaling Pathway ◽  
Early Development ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Mechanisms Of Action ◽  
Gi Tract ◽  
Hh Signaling

Hedgehog (Hh) proteins are members of a family of secreted signaling factors that orchestrate the development of many organs and tissues including those of the gastrointestinal (GI) tract. The requirement for Hh activity is not limited to early development but underlies the homeostasis of a number of tissues, and abnormal activity of the Hh pathway is associated with several GI malignancies. Understanding the roles and mechanisms of action of Hh signaling both in development and postnatally should thus give novel insights into potential treatments for these diseases. Here we focus on the Hh signaling pathway and its role in GI tract development and maintenance and consider the diseases resulting from aberrant Hh activity.

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.

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