Temporal effects of Notch signaling and potential cooperation with multiple downstream effectors on adenohypophysis cell specification in zebrafish

AbstractUnlike mammals, zebrafish can regenerate a damaged retina. Key to this regenerative response are Müller glia (MG) that divide and produce progenitors for retinal repair. Although factors regulating MG’s decision to divide remain mostly unknown, a certain threshold of neuron death must be exceeded in order for MG to engage in a regenerative response. A role for Notch signaling in this process is indicated since its inhibition expands the zone of injury-responsive MG following a focal injury. Our data show that injury-dependent changes in Dll4 and Dlb control Notch signaling in MG and that Hey1 and Id2b are downstream effectors that regulate proliferation of MG and MG-derived progenitors. Although we find Hey1 and Id2b can inhibit proliferation of MG-derived progenitors, only Hey1 is able to regulate MG’s injury response threshold. Remarkably, Hey1 suppression is sufficient to recapitulate the effects of Notch inhibition on MG’s injury response threshold.

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Faculty Opinions recommendation of T-cell factor 1 is a gatekeeper for T-cell specification in response to Notch signaling.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13434971.14811111 ◽

2012 ◽

Author(s):

Harald von Boehmer ◽

Taras Kreslavsky

Keyword(s):

T Cell ◽

Notch Signaling ◽

Cell Specification ◽

T Cell Factor

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Bcl11b and combinatorial resolution of cell fate in the T-cell gene regulatory network

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1610617114 ◽

2017 ◽

Vol 114 (23) ◽

pp. 5800-5807 ◽

Cited By ~ 39

Author(s):

William J. R. Longabaugh ◽

Weihua Zeng ◽

Jingli A. Zhang ◽

Hiroyuki Hosokawa ◽

Camden S. Jansen ◽

...

Keyword(s):

Transcription Factors ◽

T Cell ◽

Notch Signaling ◽

Gene Regulatory Network ◽

Cell Fate ◽

Regulatory Network ◽

T Cell Development ◽

Cell Specification ◽

Gene Regulatory

T-cell development from hematopoietic progenitors depends on multiple transcription factors, mobilized and modulated by intrathymic Notch signaling. Key aspects of T-cell specification network architecture have been illuminated through recent reports defining roles of transcription factors PU.1, GATA-3, and E2A, their interactions with Notch signaling, and roles of Runx1, TCF-1, and Hes1, providing bases for a comprehensively updated model of the T-cell specification gene regulatory network presented herein. However, the role of lineage commitment factor Bcl11b has been unclear. We use self-organizing maps on 63 RNA-seq datasets from normal and perturbed T-cell development to identify functional targets of Bcl11b during commitment and relate them to other regulomes. We show that both activation and repression target genes can be bound by Bcl11b in vivo, and that Bcl11b effects overlap with E2A-dependent effects. The newly clarified role of Bcl11b distinguishes discrete components of commitment, resolving how innate lymphoid, myeloid, and dendritic, and B-cell fate alternatives are excluded by different mechanisms.

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Leptin and Notch Signaling Cooperate in Sustaining Glioblastoma Multiforme Progression

Biomolecules ◽

10.3390/biom10060886 ◽

2020 ◽

Vol 10 (6) ◽

pp. 886

Author(s):

Salvatore Panza ◽

Umberto Russo ◽

Francesca Giordano ◽

Antonella Leggio ◽

Ines Barone ◽

...

Keyword(s):

Glioblastoma Multiforme ◽

Notch Signaling ◽

Dominant Negative ◽

Biologically Active ◽

Gamma Secretase ◽

Leptin Receptors ◽

Downstream Effectors ◽

Enhanced Expression ◽

Forming Efficiency ◽

The Central Nervous System

Glioblastoma multiforme (GBM) is the most malignant form of glioma, which represents one of the commonly occurring tumors of the central nervous system. Despite the continuous development of new clinical therapies against this malignancy, it still remains a deadly disease with very poor prognosis. Here, we demonstrated the existence of a biologically active interaction between leptin and Notch signaling pathways that sustains GBM development and progression. We found that the expression of leptin and its receptors was significantly higher in human glioblastoma cells, U-87 MG and T98G, than in a normal human glial cell line, SVG p12, and that activation of leptin signaling induced growth and motility in GBM cells. Interestingly, flow cytometry and real-time RT-PCR assays revealed that GBM cells, grown as neurospheres, displayed stem cell-like properties (CD133+) along with an enhanced expression of leptin receptors. Leptin treatment significantly increased the neurosphere forming efficiency, self-renewal capacity, and mRNA expression levels of the stemness markers CD133, Nestin, SOX2, and GFAP. Mechanistically, we evidenced a leptin-mediated upregulation of Notch 1 receptor and the activation of its downstream effectors and target molecules. Leptin-induced effects on U-87 MG and T98G cells were abrogated by the selective leptin antagonist, the peptide LDFI (Leu-Asp-Phe-Ile), as well as by the specific Notch signaling inhibitor, GSI (Gamma Secretase Inhibitor) and in the presence of a dominant-negative of mastermind-like-1. Overall, these findings demonstrate, for the first time, a functional interaction between leptin and Notch signaling in GBM, highlighting leptin/Notch crosstalk as a potential novel therapeutic target for GBM treatment.

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Maintenance of T Cell Specification and Differentiation Requires Recurrent Notch Receptor–Ligand Interactions

Journal of Experimental Medicine ◽

10.1084/jem.20040394 ◽

2004 ◽

Vol 200 (4) ◽

pp. 469-479 ◽

Cited By ~ 236

Author(s):

Thomas M. Schmitt ◽

Maria Ciofani ◽

Howard T. Petrie ◽

Juan Carlos Zúñiga-Pflücker

Keyword(s):

T Cell ◽

Notch Signaling ◽

Cell Fate ◽

Stromal Cells ◽

Cell Lineage ◽

Notch Receptor ◽

Lineage Specification ◽

Cell Specification ◽

Receptor Ligand ◽

Ligand Interactions

Notch signaling has been shown to play a pivotal role in inducing T lineage commitment. However, T cell progenitors are known to retain other lineage potential long after the first point at which Notch signaling is required. Thus, additional requirements for Notch signals and the timing of these events relative to intrathymic differentiation remain unknown. Here, we address this issue by culturing subsets of CD4 CD8 double negative (DN) thymocytes on control stromal cells or stromal cells expressing Delta-like 1 (Dll1). All DN subsets were found to require Notch signals to differentiate into CD4+ CD8+ T cells. Using clonal analyses, we show that CD44+ CD25+ (DN2) cells, which appeared committed to the T cell lineage when cultured on Dll1-expressing stromal cells, nonetheless gave rise to natural killer cells with a progenitor frequency similar to that of CD44+ CD25− (DN1) thymocytes when Notch signaling was absent. These data, together with the observation that Dll1 is expressed on stromal cells throughout the thymic cortex, indicates that Notch receptor–ligand interactions are necessary for induction and maintenance of T cell lineage specification at both the DN1 and DN2 stages of T cell development, suggesting that the Notch-induced repression of the B cell fate is temporally separate from Notch-induced commitment to the T lineage.

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