scholarly journals Prdm16 and Notch functionally and physically interact during artery development

2021 ◽  
Author(s):  
Manu Beerens ◽  
Jore Van Wauwe ◽  
Sander Craps ◽  
Margo Daems ◽  
KC Ashmita ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Notch Signaling ◽  
Circulatory System ◽  
Bhlh Transcription Factor ◽  
Vascular Disorders ◽  
Notch Activity ◽  
Related Family ◽  
Downstream Effector ◽  
Arterial Development

ABSTRACTRationaleProper functionality of the circulatory system requires correct arteriovenous (AV) endothelial cell (EC) differentiation. While Notch signaling and its downstream effector Hes- Related Family bHLH Transcription Factor with YRPW Motif (Hey)2 favor arterial specification, transcription factor (TF) chicken ovalbumin upstream transcription factor 2 (Coup-TFII) inhibits canonical Notch activity to induce venous identity. However, transcriptional programs that compete with Coup-TFII to orchestrate arterial specification upstream of Notch remain largely unknown. We identified positive regulatory domain-containing protein (Prdm)16 as an arterial EC- specific TF, but its role during arterial EC specification and development remains unexplored.ObjectiveTo unravel the role of Prdm16 during arterial endothelial lineage specification and artery formation.Methods and ResultsTranscriptomic data of freshly isolated arterial and venous ECs from humans and mice revealed that Prdm16 is exclusively expressed by arterial ECs throughout development. This expression pattern was independent of hemodynamic factors and conserved in zebrafish. Accordingly, loss of prdm16 in zebrafish perturbed AV endothelial specification and caused AV malformations in an EC-autonomous manner. This coincided with reduced canonical Notch activity in arterial ECs and was amplified when prdm16 and notch pathway members were concomitantly knocked down. In vitro studies further indicated that Prdm16 not only amplified Notch signaling, but also physically and functionally interacted with Hey2 to drive proper arterial specification.ConclusionWe showed that Prdm16 plays a pivotal role during arterial development through its physical and functional interaction with canonical Notch. As both Hey2 and Prdm16 have been associated with diverse vascular disorders including migraine and atherosclerosis, Prdm16 represents an attractive new target to treat these vascular disorders.

scholarly journals The bHLH Transcription Factor NeuroD Governs Photoreceptor Genesis and Regeneration Through Delta-Notch Signaling

2015 ◽  
Vol 56 (12) ◽  
pp. 7496 ◽  
Author(s):  
Scott M. Taylor ◽  
Karen Alvarez-Delfin ◽  
Carole J. Saade ◽  
Jennifer L. Thomas ◽  
Ryan Thummel ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Notch Signaling ◽  
Bhlh Transcription Factor

scholarly journals NBS1 interacts with Notch signaling in neuronal homeostasis

2020 ◽  
Vol 48 (19) ◽  
pp. 10924-10939
Author(s):  
Zhong-Wei Zhou ◽  
Murat Kirtay ◽  
Nadine Schneble ◽  
George Yakoub ◽  
Mingmei Ding ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Notch Pathway ◽  
Direct Consequence ◽  
Nijmegen Breakage Syndrome ◽  
Neuron Development ◽  
Genetic Ablation ◽  
Notch Activity ◽  
And Migration

Abstract NBS1 is a critical component of the MRN (MRE11/RAD50/NBS1) complex, which regulates ATM- and ATR-mediated DNA damage response (DDR) pathways. Mutations in NBS1 cause the human genomic instability syndrome Nijmegen Breakage Syndrome (NBS), of which neuronal deficits, including microcephaly and intellectual disability, are classical hallmarks. Given its function in the DDR to ensure proper proliferation and prevent death of replicating cells, NBS1 is essential for life. Here we show that, unexpectedly, Nbs1 deletion is dispensable for postmitotic neurons, but compromises their arborization and migration due to dysregulated Notch signaling. We find that Nbs1 interacts with NICD-RBPJ, the effector of Notch signaling, and inhibits Notch activity. Genetic ablation or pharmaceutical inhibition of Notch signaling rescues the maturation and migration defects of Nbs1-deficient neurons in vitro and in vivo. Upregulation of Notch by Nbs1 deletion is independent of the key DDR downstream effector p53 and inactivation of each MRN component produces a different pattern of Notch activity and distinct neuronal defects. These data indicate that neuronal defects and aberrant Notch activity in Nbs1-deficient cells are unlikely to be a direct consequence of loss of MRN-mediated DDR function. This study discloses a novel function of NBS1 in crosstalk with the Notch pathway in neuron development.

scholarly journals TWIST1 Heterodimerization with E12 Requires Coordinated Protein Phosphorylation to Regulate Periostin Expression

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1392
Author(s):  
Svetlana A. Mikheeva ◽  
Nathan D. Camp ◽  
Lei Huang ◽  
Antrix Jain ◽  
Sung Yun Jung ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Invasion ◽  
Glioma Cells ◽  
Therapeutic Strategies ◽  
Bhlh Transcription Factor ◽  
Phosphorylation Sites ◽  
Wild Type ◽  
Dismal Prognosis ◽  
Adjacent Brain

Diffuse invasion into adjacent brain matter by glioblastoma (GBM) is largely responsible for their dismal prognosis. Previously, we showed that the TWIST1 (TW) bHLH transcription factor and its regulated gene periostin (POSTN) promote invasive phenotypes of GBM cells. Since TW functional effects are regulated by phosphorylation and dimerization, we investigated how phosphorylation of serine 68 in TW regulates TW dimerization, POSTN expression, and invasion in glioma cells. Compared with wild-type TW, the hypophosphorylation mutant, TW(S68A), impaired TW heterodimerization with the E12 bHLH transcription factor and cell invasion in vitro but had no effect on TW homodimerization. Overexpression of TW:E12 forced dimerization constructs (FDCs) increased glioma cell invasion and upregulated pro-invasive proteins, including POSTN, in concert with cytoskeletal reorganization. By contrast, TW:TW homodimer FDCs inhibited POSTN expression and cell invasion in vitro. Further, phosphorylation of analogous PXSP phosphorylation sites in TW:E12 FDCs (TW S68 and E12 S139) coordinately regulated POSTN and PDGFRa mRNA expression. These results suggested that TW regulates pro-invasive phenotypes in part through coordinated phosphorylation events in TW and E12 that promote heterodimer formation and regulate downstream targets. This new mechanistic understanding provides potential therapeutic strategies to inhibit TW-POSTN signaling in GBM and other cancers.

scholarly journals TWIST2 and the PPAR signaling pathway are important in the progression of nonalcoholic steatohepatitis

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Yanmei Zhang ◽  
Xiaoxiao Ge ◽  
Yongqing Li ◽  
Bingyang Zhang ◽  
Peijun Wang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Fatty Liver ◽  
Rna Sequencing ◽  
Nonalcoholic Steatohepatitis ◽  
In Vitro Model ◽  
Bhlh Transcription Factor ◽  
Protein Levels ◽  
Ppar Signaling ◽  
Vitro Model

Abstract Background To investigate the roles of the transcription factors twist family bHLH transcription factor 1 (TWIST1), twist family bHLH transcription factor 2 (TWIST2), and peroxisome proliferator activated receptor gamma (PPARγ) in the progression of nonalcoholic steatohepatitis. Methods The protein levels of TWIST1, TWIST2 and PPARγ were determined in the serum of nonalcoholic fatty liver disease (NAFLD) patients and healthy controls by enzyme-linked immunosorbent assay (ELISA). An in vivo model for fatty liver was established by feeding C57BL/6 J mice a high-fat diet (HFD). An in vitro model of steatosis was established by treating LO-2 cells with oleic acid (OA). RNA sequencing was performed on untreated and OA-treated LO-2 cells followed by TWIST1, TWIST2 and PPARγ gene mRNA levels analysis, Gene Ontology (GO) enrichment and pathway analysis. Results The TWIST2 serum protein levels decreased significantly in all fatty liver groups (P < 0.05), while TWIST1 varied. TWIST2 tended to be lower in mice fed an HFD and was significantly lower at 3 months. Similarly, in the in vitro model, the TWIST2 protein level was downregulated significantly at 48 and 72 h after OA treatment. RNA sequencing of LO-2 cells showed an approximately 2.3-fold decrease in TWIST2, with no obvious change in TWIST1 and PPARγ. The PPAR signaling pathway was enriched, with 4 genes upregulated in OA-treated cells (P = 0.0018). The interleukin (IL)-17 and tumor necrosis factor (TNF) signaling pathways were enriched in OA-treated cells. Conclusions The results provide evidence that the TWIST2 and PPAR signaling pathways are important in NAFLD and shed light on a potential mechanism of steatosis.

scholarly journals The N terminus of Ascl1 underlies differing proneural activity of mouse and Xenopus Ascl1 proteins

2018 ◽  
Vol 3 ◽  
pp. 125 ◽  
Author(s):  
Laura J.A. Hardwick ◽  
Anna Philpott
Keyword(s):  
Transcription Factor ◽  
Bhlh Transcription Factor ◽  
Protein Accumulation ◽  
Primary Neuron ◽  
Helix Loop Helix ◽  
N Terminus ◽  
Specific Regulation ◽  
Species Specific

The proneural basic-helix-loop-helix (bHLH) transcription factor Ascl1 is a master regulator of neurogenesis in both central and peripheral nervous systems in vivo, and is a central driver of neuronal reprogramming in vitro. Over the last three decades, assaying primary neuron formation in Xenopus embryos in response to transcription factor overexpression has contributed to our understanding of the roles and regulation of proneural proteins like Ascl1, with homologues from different species usually exhibiting similar functional effects. Here we demonstrate that the mouse Ascl1 protein is twice as active as the Xenopus protein in inducing neural-β-tubulin expression in Xenopus embryos, despite there being little difference in protein accumulation or ability to undergo phosphorylation, two properties known to influence Ascl1 function. This superior activity of the mouse compared to the Xenopus protein is dependent on the presence of the non-conserved N terminal region of the protein, and indicates species-specific regulation that may necessitate care when interpreting results in cross-species experiments.

scholarly journals The bHLH transcription factor Ascl1a is essential for the specification of the intestinal secretory cells and mediates Notch signaling in the zebrafish intestine

2013 ◽  
Vol 376 (2) ◽  
pp. 187-197 ◽  
Author(s):  
Lydie C. Flasse ◽  
David G. Stern ◽  
Justine L. Pirson ◽  
Isabelle Manfroid ◽  
Bernard Peers ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Notch Signaling ◽  
Secretory Cells ◽  
Bhlh Transcription Factor

scholarly journals Disruption of CK2β in Embryonic Neural Stem Cells Compromises Proliferation and Oligodendrogenesis in the Mouse Telencephalon

2010 ◽  
Vol 30 (11) ◽  
pp. 2737-2749 ◽  
Author(s):  
Emmanuelle Huillard ◽  
Léa Ziercher ◽  
Olivier Blond ◽  
Michael Wong ◽  
Jean-Christophe Deloulme ◽  
...  
Keyword(s):  
Transcription Factor ◽  
System Development ◽  
Nervous System Development ◽  
Conditional Knockout ◽  
Regulatory Subunit ◽  
Bhlh Transcription Factor ◽  
Helix Loop Helix ◽  
Proliferation And Differentiation

ABSTRACT Genetic programs that govern neural stem/progenitor cell (NSC) proliferation and differentiation are dependent on extracellular cues and a network of transcription factors, which can be regulated posttranslationally by phosphorylation. However, little is known about the kinase-dependent pathways regulating NSC maintenance and oligodendrocyte development. We used a conditional knockout approach to target the murine regulatory subunit (beta) of protein kinase casein kinase 2 (CK2β) in embryonic neural progenitors. Loss of CK2β leads to defects in proliferation and differentiation of embryonic NSCs. We establish CK2β as a key positive regulator for the development of oligodendrocyte precursor cells (OPCs), both in vivo and in vitro. We show that CK2β directly interacts with the basic helix-loop-helix (bHLH) transcription factor Olig2, a critical modulator of OPC development, and activates the CK2-dependent phosphorylation of its serine-threonine-rich (STR) domain. Finally, we reveal that the CK2-targeted STR domain is required for the oligodendroglial function of Olig2. These findings suggest that CK2 may control oligodendrogenesis, in part, by regulating the activity of the lineage-specific transcription factor Olig2. Thus, CK2β appears to play an essential and uncompensated role in central nervous system development.

The AP-2 transcription factor is required for joint formation and cell survival in Drosophila leg development

Development ◽  
2001 ◽  
Vol 128 (8) ◽  
pp. 1231-1238 ◽  
Author(s):  
B. Kerber ◽  
I. Monge ◽  
M. Mueller ◽  
P.J. Mitchell ◽  
S.M. Cohen
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
Notch Signaling ◽  
Cell Survival ◽  
Leg Length ◽  
Notch Activity ◽  
Support Cell ◽  
Important Mediator ◽  
Leg Development ◽  
Severe Reduction

Flies mutant for the Drosophila homologue of the mammalian transcription factor AP-2 show a severe reduction in leg length and fail to develop joint structures. Presumptive joint cells express dAP-2 in response to Notch signaling. dAP-2 is required for joint cell differentiation and can induce formation of supernumerary joints when misexpressed. Although dAP-2 is expressed only in presumptive joint cells, its activity is required to support cell survival in the entire leg segment. Taken together, our data indicate that dAP-2 is an important mediator of Notch activity in leg development.

The transcription factor dHAND is a downstream effector of BMPs in sympathetic neuron specification

Development ◽  
2000 ◽  
Vol 127 (18) ◽  
pp. 4073-4081 ◽  
Author(s):  
M.J. Howard ◽  
M. Stanke ◽  
C. Schneider ◽  
X. Wu ◽  
H. Rohrer
Keyword(s):  
Transcription Factor ◽  
Bone Morphogenetic Proteins ◽  
Sympathetic Neurons ◽  
Sympathetic Neuron ◽  
Sympathetic Ganglia ◽  
Catecholaminergic Neurons ◽  
Helix Loop Helix ◽  
Downstream Effector

The dHAND basic helix-loop-helix transcription factor is expressed in neurons of sympathetic ganglia and has previously been shown to induce the differentiation of catecholaminergic neurons in avian neural crest cultures. We now demonstrate that dHAND expression is sufficient to elicit the generation of ectopic sympathetic neurons in vivo. The expression of the dHAND gene is controlled by bone morphogenetic proteins (BMPs), as suggested by BMP4 overexpression in vivo and in vitro, and by noggin-mediated inhibition of BMP function in vivo. The timing of dHAND expression in sympathetic ganglion primordia, together with the induction of dHAND expression in response to Phox2b implicate a role for dHAND as transcriptional regulator downstream of Phox2b in BMP-induced sympathetic neuron differentiation.

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