scholarly journals CCRL2 Modulates Physiological and Pathological Angiogenesis During Retinal Development

2021 ◽  
Vol 9 ◽  
Author(s):  
Cyrine Ben Dhaou ◽  
Annalisa Del Prete ◽  
Silvano Sozzani ◽  
Marc Parmentier
Keyword(s):  
Intracellular Signaling ◽  
Cell Types ◽  
Mouse Retina ◽  
Dependent Manner ◽  
Newborn Mice ◽  
Multifunctional Protein ◽  
Intracellular Signaling Pathway ◽  
Pathological Angiogenesis ◽  
Oxygen Induced Retinopathy ◽  
Inflammatory Stimuli

Chemerin is a multifunctional protein involved in the regulation of inflammation, metabolism, and tumorigenesis. It binds to three receptors, CMKLR1, GPR1 and CCRL2. CMKLR1 is a fully functional receptor mediating most of the known activities of chemerin. CCRL2 does not seem to couple to any intracellular signaling pathway and is presently considered as an atypical receptor able to present the protein to cells expressing CMKLR1. CCRL2 is expressed by many cell types including leukocyte subsets and endothelial cells, and its expression is strongly upregulated by inflammatory stimuli. We recently reported that chemerin can negatively regulate the angiogenesis process, including during the development of the vascular network in mouse retina. The role of CCRL2 in angiogenesis was unexplored so far. In the present work, we demonstrate that mice lacking CCRL2 exhibit a lower density of vessels in the developing retina and this phenotype persists in adulthood, in a CMKLR1-dependent manner. Vascular sprouting was not affected, while vessel pruning, and endothelial cell apoptosis were increased. Pathological angiogenesis was also reduced in CCRL2-/- mice in a model of oxygen-induced retinopathy. The phenotype closely mimics that of mice overexpressing chemerin, and the concentration of chemerin was found elevated in the blood of newborn mice, when the retinal vasculature develops. CCRL2 appears therefore to regulate the distribution and concentration of chemerin in organs, regulating thereby its bioactivity.

scholarly journals OR1D2 receptor mediates bourgeonal-induced human CatSper activation in a G-protein dependent manner

2019 ◽  
Author(s):  
Yi-min Cheng ◽  
Tao Luo ◽  
Zhen Peng ◽  
Hou-yang Chen ◽  
Jin Zhang ◽  
...  
Keyword(s):  
G Protein ◽  
Olfactory Receptor ◽  
Intracellular Signaling ◽  
Calcium Influx ◽  
Human Sperm ◽  
Camp Level ◽  
Dependent Manner ◽  
Intracellular Signaling Pathway ◽  
Camp Pathway ◽  
Sperm Chemotaxis

AbstractDuring fertilization, sperm are guided towards eggs by physiological chemokines, a process named sperm chemotaxis. Human sperm chemotaxis is speculated to be mediated by olfactory receptor OR1D2 in a pathway requiring calcium influx. Bourgeonal, an artificial ligand of OR1D2, can activate CatSper, the primary calcium channel in human sperm. However, whether bourgeonal-induced CatSper activation requires OR1D2 and how CatSper is activated remain unclear. Herein, we show that OR1D2 antibody can inhibit bourgeonal-induced CatSper activation and sperm chemotaxis, proving that OR1D2 mediates bourgeonal-induced CatSper activation. Furthermore, bourgeonal-evoked CatSper currents can be greatly suppressed by either GDP-β-S or antibody of Gαs. Interestingly, bourgeonal can transiently increase sperm cAMP level, and this effect can be abolished by OR1D2 antibody. Consistently, bourgeonal-induced CatSper activation can be inhibited by membrane adenylate cyclases inhibitor. Overall, our results indicate that bourgeonal activates CatSper via OR1D2-G protein-cAMP pathway. Although CatSper can be activated by various physiological and environmental factors, this study represents the most recent progress proving that CatSper can be indirectly activated by extracellular regulators through a G-protein-dependent intracellular signaling pathway.

Glucocorticoid negative feedback in sheep corticotrophs: a comparison with AtT-20 corticotroph tumor cells

1994 ◽  
Vol 267 (2) ◽  
pp. R463-R469
Author(s):  
T. P. Clark ◽  
R. J. Kemppainen
Keyword(s):  
Protein Kinase ◽  
Calcium Channel ◽  
Negative Feedback ◽  
Intracellular Signaling ◽  
Glucocorticoid Receptors ◽  
Mechanistic Model ◽  
Cell Types ◽  
Dependent Manner ◽  
Acth Secretion ◽  
Acth Release

Early glucocorticoid feedback in sheep anterior pituitary (AP) cells was compared and contrasted with that in mouse pituitary tumor AtT-20 cells. Dexamethasone (DEX) inhibited corticotropin-releasing hormone (CRH)-stimulated adrenocorticotropin (ACTH) release in a concentration- and time-dependent manner with similar potency amongst cell types. This inhibition was mediated through type II glucocorticoid receptors and required the synthesis of new protein. However, stimulation of protein kinase C with phorbol 12-myristate 13-acetate (PMA) resulted in greater ACTH release and greater inhibition by DEX in sheep AP cells. In contrast to sheep AP cells, AtT-20 cells were insensitive to glucocorticoids when secretion was stimulated by KCl depolarization or the voltage-dependent calcium channel agonist, maitotoxin (MTX). In both cell types, CRH-, KCl-, and MTX-stimulated ACTH release was inhibited by the calcium channel blocker, nifedipine (NIF). Whereas NIF also inhibited PMA-induced ACTH secretion in AtT-20 cells, it did not in sheep AP cells. These data demonstrate that early glucocorticoid feedback is operative in sheep corticotrophs and that AtT-20 cells appear to serve as an appropriate mechanistic model for aspects of negative feedback when the CRH-protein kinase A pathway is activated but may not be appropriate when ACTH secretion is activated via other intracellular signaling pathways.

314 PARTHENOGENETIC ACTIVATION OF PORCINE OOCYTES AT THE MII STAGE BY Ca-EDTA TREATMENT

2006 ◽  
Vol 18 (2) ◽  
pp. 264
Author(s):  
H. Kawase ◽  
H. Imai ◽  
M. Yamada
Keyword(s):  
Intracellular Signaling ◽  
Metal Ion ◽  
Germinal Vesicle ◽  
Cumulus Cells ◽  
Optimal Time ◽  
Dependent Manner ◽  
Rapid Reduction ◽  
Parthenogenetic Activation ◽  
Intracellular Signaling Pathway ◽  
Edta Treatment

We previously found that treatment of porcine oocytes at the germinal vesicle (GV) stage with a cell membrane-impermeable metal ion chelator, EDTA saturated with Ca2+ (Ca-EDTA, 1 mM), induced artificial activation followed by formation of a pronucleus (PN) (Azuma et al. 2001 Biol. Reprod. 64, 647-653). In our preliminary experiments, it was found that oocytes at the metaphase of the second meiotic division (MII) are activated by Ca-EDTA treatment, leading to formation of PN and development to the blastocyst stage, and that it takes about 30 h for the oocytes to form PN by Ca-EDTA treatment. Normally, the optimal time for MII oocytes to be activated by sperm or conventionally used activation stimuli such as Ca2+ ionophore is much shorter than that in Ca-EDTA and prolonged arrest of the oocytes leads to aging. In this study, we examined how MII porcine oocytes were activated by Ca-EDTA treatment. To obtain MII oocytes, immature porcine oocytes enclosed by cumulus cells from ovaries of gilts were cultured in TCM-199 + NaHCO3 + Na pyruvate + pregnant mare serum conadotropin (PMSG) + hCG (199 medium) at 38�C under 5% CO2 in air for 48 h. First, to elucidate an intracellular signaling pathway required for Ca-EDTA induced activation, MII oocytes were cultured for 36 h in 199 medium containing Ca-EDTA (1 mM) with or without each inhibitor as follows, calphostin C (PKC inhibitor, 1 �M), U73122 (phospholipase C (PLC) inhibitor, 10 �M), PD98059 (MAPK inhibitor, 50 �M), and BAPTA-AM (intracellular Ca2+ chelator, 50 �M). Of the oocytes treated with Ca-EDTA, 60% underwent PN formation, whereas none of oocytes kept in medium alone was activated. Concomitant addition of BAPTA-AM to 199 medium with Ca-EDTA inhibited PN formation, whereas other inhibitors had no effects. These results suggest that a sufficient amount of intracellular calcium ion is necessary for parthenogenetic activation of porcine oocytes by Ca-EDTA, and that the activation may be independent on the mobilization of Ca2+ by PLC activation. Next, we analyzed changes of maturation-promoting factor (MPF) and MAPK activities in the oocytes during 48 h of culture in 199 medium with or without Ca-EDTA. Both kinases were measured by assays of the phosphorylation of histone H1 and myelin basic protein (MBP), respectively. When MII oocytes were cultured in 199 medium without Ca-EDTA, MPF and MAPK activities in oocytes were high at the onset of culture, and then gradually decreased as the oocytes underwent aging until 48 h of culture. On the other hand, in the Ca-EDTA treated oocytes, MPF and MAPK activities were maintained at high levels similar to those in oocytes at the onset of culture until 18 h or 24 h, respectively, and then both activities rapidly decreased. The timing of the rapid reduction of MAPK activity almost coincided with the time when PN formation was started. These results indicate that Ca-EDTA regulates MPF and MAPK activities in porcine oocytes during a prolonged period of culture from the MII stage to induce PN formation in a Ca2+-dependent manner.

Abstract 130: Il-6 Mediates Vein Wall Response to Thrombosis in a Model Dependent Manner

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Andrea T Obi ◽  
Andrew Kimball ◽  
Megan Elfline ◽  
Catherine Luke ◽  
Jose Diaz ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Intracellular Signaling ◽  
Therapeutic Option ◽  
Vena Cava ◽  
Dependent Manner ◽  
Vein Wall ◽  
Cell Recruitment ◽  
Intracellular Signaling Pathway ◽  
Downstream Signaling ◽  
Genetic Deletion

Background: Venous thrombosis (VT) and the vein wall responses may be related to interleukin 6 (IL-6) signaling in humans and mice. Inflammatory and fibrotic effects of IL-6 largely signal through the trans pathway: IL-6/soluble IL-6Rα complex associates with ubiquitously expressed signal transducing protein gp130. We hypothesized that IL-6 signaling would differ depending upon thrombosis mechanism (complete v. partial stasis), and disruption of IL-6/IL-6Rα/gp130 axis would alter vein wall response to VT. Methods: Wild type C57BL/6 or IL-6-/- mice underwent induction of VT via inferior vena cava (IVC) stenosis (partial stasis) or ligation (complete stasis). Select WT mice received sgp130Fc chimera to inhibit trans pathway signaling. Vein wall, thrombus, and plasma were harvested at various time points and analyzed by PCR, western blot, ELISA or immunohistochemistry. Results: Compared to sham animals, those undergoing VT (complete or partial stasis) exhibited elevated vein wall IL-6 on post-VT day 4 (n=6-9, p<0.0001) but only complete stasis also had significantly elevated IL-6Rα (n=6-9, p<0.0001) and downstream intracellular signaling pathway molecule pSTAT3 (n=6-9, p=0.0002). Complete stasis VT in IL-6-/- mice was characterized by decreased circulating gp130 (n=4-6 p=0.0257), similar size thrombi to WT controls (0.020±0.005 v. 0.023±0.006, p=ns), and decreased CD68+ macrophage recruitment to the vein wall (n=3-5, p=0.0279). The IL-6-/- mice were protected from endothelial to mesenchymal-like transformation, as reflected by decreased FSP-1 (n=3-6, p<0.0001) and increased VE cadherin (n=3-6, p=0.0421) as compared with WT. Disruption of trans-signaling pathway via gp130Fc chimera resulted in less vein IL-6 (n=6-7, p=0.0027), TGF-β (n=6-7, p=0.0094), and decreased CD68 cell recruitment (n=3, p=0.0299). Conclusions: Experimental VT stimulates IL-6 and downstream signaling processes and is dependent on the mechanism of thrombosis. Genetic deletion of IL-6 and selective disruption of trans-signaling pathway by sgp130 decreases vein wall inflammation and influences vein wall remodeling. Targeting of IL-6 trans-signaling pathway may represent a therapeutic option to treat vein wall inflammation post thrombosis.

scholarly journals B7-H1(PD-L1) confers chemoresistance through ERK and p38 MAPK pathway in tumor cells

2018 ◽  
Author(s):  
Xiaosheng Wu ◽  
Yanli Li ◽  
Xin Liu ◽  
Siyu Cao ◽  
Susan M. Harrington ◽  
...  
Keyword(s):  
Tumor Cells ◽  
P38 Mapk ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Dependent Manner ◽  
Intracellular Signaling Pathway ◽  
Development Of Resistance ◽  
P38 Mapk Pathway

ABSTRACTDevelopment of resistance to chemotherapy and immunotherapy is a major obstacle in extending the survival of patients with cancer. Although several molecular mechanisms have been identified that can contribute to chemoresistance, the role of immune checkpoint molecules in tumor chemoresistance remains underestimated. It has been recently observed that overexpression of B7-H1(PD-L1) confers chemoresistance in human cancers, however the underlying mechanisms are unclear. Here we show that the development of chemoresistance depends on the increased activation of ERK pathway in tumor cells overexpressing B7-H1. Conversely, B7-H1 deficiency renders tumor cells susceptible to chemotherapy in a cell-context dependent manner through activation of the p38 MAPK pathway. B7-H1 in tumor cells associates with the catalytic subunit of a DNA-dependent serine / threonine protein kinase (DNA-PKcs). DNA-PKcs is required for the activation of ERK or p38 MAPK in tumors expressing B7-H1, but not in B7-H1 negative or B7-H1 deficient tumors. Ligation of B7-H1 by anti-B7-H1 monoclonal antibody (H1A) increased the sensitivity of human triple negative breast tumor cells to cisplatin therapy in vivo. Our results suggest that B7-H1(PD-L1) expression in cancer cells modifies their chemosensitivity towards certain drugs and targeting B7-H1 intracellular signaling pathway is a new way to overcome cancer chemoresistance.

Role of macrophage SR-BI class a scavenger receptor in atherosclerosis: Crosstalk TLR4/NF-KB/ signaling pathway activation   

2019 ◽  
Vol 7 (4) ◽  
pp. 298-309
Author(s):  
Jilin Wang ◽  
Jeffrey D. Juan
Keyword(s):  
Signaling Pathways ◽  
Adhesion Molecule ◽  
Intracellular Signaling ◽  
Scavenger Receptor ◽  
Cell Types ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Inflammatory Stimuli ◽  
Class B ◽  
Tlr4 Activation

Atherosclerosis is an inflammatory disease, and one of the culprits may be infections caused by pathogens, that may be linked to development and progression of atherosclerosis by several mechanisms. Class B scavenger receptor BI (SR-BI), an HDL receptor, SR-BI is expressed in a variety of cell types, most abundantly in steroidogenic cells and in the liver. SR-BI is also expressed in macrophages has been shown to mediate the cellular uptake of certain bacteria and may therefore play an important role in innate immunity. The innate immune response and the homeostatic network controlling cellular sterol are important implications for several common diseases, including atherosclerosis. The TLR4-independent SR-BI signaling in macrophages and the implication for its role in atherosclerosis has not yet to be investigated. Our data showed that mice lacking SR-BI are highly sensitive to form atherosclerosis than wild type mice. In addition, we showed that SR-BI-/- mice attenuated proinflammatory cytokines and chemokine response to LPS. The LPS-induced cytokine expression in both WT and SR-BI-/- was dependent on NFκB signaling pathways. One possibility is that an interaction between SR-BI and the TLR4 complex might modulate TLR4 activation and subsequent intracellular signaling pathways. The interaction of HDL and SR-BI in endothelial cells inhibits the activation of NFκB and subsequent expression of the adhesion molecules vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 to inflammatory stimuli. We conclude that SR-BI plays an important function in the atherosclerosis mechanism.

In situ calcium mapping in the mouse retina via time-of-flight secondary ion mass spectrometry: modulation of retinal angiogenesis by calcium ion in development and oxygen-induced retinopathy

2008 ◽  
Vol 86 (5) ◽  
pp. 459-467 ◽  
Author(s):  
Jeong Hun Kim ◽  
Jin Hyoung Kim ◽  
Young Suk Yu ◽  
Dong Hun Kim ◽  
Tae Geol Lee ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Calcium Ion ◽  
Secondary Ion Mass Spectrometry ◽  
Time Of Flight ◽  
Mouse Retina ◽  
Pathological Angiogenesis ◽  
Oxygen Induced Retinopathy ◽  
Tof Sims ◽  
Ion Mass Spectrometry ◽  
Secondary Ion

Pathological angiogenesis in the eye is the most common cause of blindness in all age groups. In physiological and pathological cellular processes including angiogenesis, ion homeostasis is greatly affected. This study is to investigate the role of calcium ion in physiological and pathological angiogenesis in the retina, which is based on the results of ion mapping by time-of-flight secondary ion mass spectrometry (TOF-SIMS). We provided that calcium distribution is the most accordant to change with physiological vessel formation of development in the retina and pathological angiogenesis of oxygen-induced retinopathy (OIR), which is supported by ion mapping in retinal tissue using TOF-SIMS. In addition to anti-proliferative and anti-angiogenic activity of the calcium inhibitor on endothelial cells, retinal neovascularization of OIR was effectively inhibited by the calcium inhibitor. Calcium ion could play a crucial role in physiological and pathological angiogenesis in the retina. Moreover, TOF-SIMS could be a good method to simultaneously evaluate the changes of variable ions of the retina in biological processes.

Up-regulated ferritin in periodontitis promotes inflammatory cytokine expression in human periodontal ligament cells through transferrin receptor via ERK/P38 MAPK pathways

2019 ◽  
Vol 133 (1) ◽  
pp. 135-148 ◽  
Author(s):  
Wenxue Huang ◽  
Yalin Zhan ◽  
Yunfei Zheng ◽  
Ye Han ◽  
Wenjie Hu ◽  
...  
Keyword(s):  
Transferrin Receptor ◽  
Intracellular Signaling ◽  
Periodontal Ligament ◽  
Periodontal Ligament Cells ◽  
Dependent Manner ◽  
Inflammatory Infiltration ◽  
Intracellular Signaling Pathway ◽  
Periodontal Tissues ◽  
Human Periodontal Ligament Cells ◽  
Tnf Α

Abstract Objective: Ferritin, an iron-binding protein, is ubiquitous and highly conserved; it plays a crucial role in inflammation, which is the main symptom of periodontitis. Full-length cDNA library analyses have demonstrated abundant expression of ferritin in human periodontal ligament. The aims of the present study were to explore how ferritin is regulated by local inflammation, and to investigate its functions and mechanisms of action in the process of periodontitis. Methods: Human gingival tissues were collected from periodontitis patients and healthy individuals. Experimental periodontitis was induced by ligature of second molars in mice. The expression of ferritin light polypeptide (FTL) and ferritin heavy polypeptide (FTH) were assessed by immunohistochemistry. Meanwhile, after stimulating human periodontal ligament cells (HPDLCs) with P. gingivalis-lipopolysaccharide (LPS), interleukin (IL)-6, and tumor necrosis factor-α (TNF-α), the expression of FTH and FTL were measured. Then, IL-6 and IL-8 were measured after incubation with different concentrations of apoferritin (iron-free ferritin) and several intracellular signaling pathway inhibitors, or after knockdown of the transferrin receptor. Results: Both FTH and FTL were substantially higher in inflamed periodontal tissues than in healthy tissues. The location of the elevated expression correlated well with the extent of inflammatory infiltration. Moreover, expression of FTH and FTL were enhanced after stimulation with P. gingivalis-LPS, IL-6, TNF-α. Apoferritin induced the production of IL-6 and IL-8 in a dose-dependent manner partly through binding to the transferrin receptor and activating ERK/P38 signaling pathways in HPDLCs. Conclusions: Ferritin is up-regulated by inflammation and exhibits cytokine-like activity in HPDLCs inducing a signaling cascade that promotes expression of pro-inflammatory cytokines associated with periodontitis.

Abstract 2638: Potentiation of Endothelin-1-induced Ca 2+ Sensitization of Myofilament after Subarachnoid Hemorrhage

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Yuichiro Kikkawa ◽  
Katsuya Hirano ◽  
Satoshi Matsuo ◽  
Akira Nakamizo ◽  
Tomio Sasaki
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Protein Kinase ◽  
Cerebral Vasospasm ◽  
Basilar Artery ◽  
Intracellular Signaling ◽  
Regulatory Protein ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Intracellular Signaling Pathway ◽  
Endothelin 1

Introduction: Increased vascular reactiveness in response to endothelin-1 (ET-1) plays an important role in the development of cerebral vasospasm. We elucidated some mechanisms of the increased vascular reactiveness to ET-1 using the basilar artery in a rabbit subarachnoid hemorrhage (SAH) model. Material & Methods: The contractile response and the expression of regulatory protein of the isolated basilar artery were evaluated. Results: ET-1 induced greater contraction than other agonists or 118 mM K + depolarization for the extent of [Ca 2+ ] i elevation, suggesting that myofilament Ca 2+ sensitivity is a greater contributor to ET-1-induced contractions than other contractions. ET-1-induced contraction of α-toxin-permeabilized strips was significantly enhanced and sustained in SAH compared to control, suggesting that the ET-1-induced myofilament Ca 2+ sensitization was potentiated after SAH. Therefore, we investigated the intracellular signaling pathway involving Rho-associated coiled-coil protein kinase (ROCK) and protein kinase C (PKC), which are two major signaling molecules that contribute to myofilament Ca 2+ sensitization. ET-1-induced contraction of α-toxin-permeabilized control strips was blocked by inhibitors to ROCK and PKC in a concentration-dependent manner, whereas the concentration-response curve shifted to the right in SAH, suggesting that ET-1-induced myofilament Ca 2+ sensitization became less sensitive to inhibitors of ROCK and PKC after SAH. The expression of PKCα, ROCK2, PKC - potentiated phosphatase inhibitor of 17 kDa (CPI-17), and myosin phosphatase target subunit 1 (MYPT1) was upregulated and the level of phosphorylation of MYPT-1 at T853, and CPI-17 at T38 was increased after SAH. ET-1 induced an enhanced and sustained elevation of the phosphorylation of MYPT1 at both T696 and T853 after SAH. Conclusion: Ca 2+ -sensitizing effect of ET-1 on myofilaments was enhanced and prolonged after SAH. The increased expression and activity of PKCα, ROCK2, CPI-17, and MYPT1 are suggested to underlie the enhanced and prolonged Ca 2+ -sensitization. ET-1-induced potentiation of myofilament Ca 2+ sensitization may cause an increased vascular reactiveness in response to ET-1 after SAH, leading to the development of cerebral vasospasm.

scholarly journals Ikaros family proteins regulate developmental windows in the mouse retina through convergent and divergent transcriptional programs

2021 ◽  
Author(s):  
Awais Javed ◽  
Pierre Mattar ◽  
Allie Cui ◽  
Michel Cayouette
Keyword(s):  
Target Genes ◽  
Cell Types ◽  
Regulatory Elements ◽  
Nervous System Development ◽  
Mouse Retina ◽  
Specific Cell ◽  
Dependent Manner ◽  
Muller Glia ◽  
Müller Glia ◽  
Hes1 Expression

ABSTRACTTemporal identity factors regulate the competence of neural progenitors to generate specific cell types in a time-dependent manner, but how they operate remains poorly defined. In the developing mouse retina, the Ikaros zinc finger transcription factor Ikzf1 regulates the production of early-born cell types, except cone photoreceptors. In this study we show that Ikzf4, another Ikaros family protein, cooperates with Ikzf1 to control cone photoreceptor production during early stages of retinal development, whereas at late stages, when Ikzf1 is no longer expressed in progenitors, Ikzf4 is instead required for Müller glia production. Using CUT&RUN sequencing, we find that both Ikzf1 and Ikzf4 generally bind to the same genes involved in cone development and other early-born fates, but at different cis-regulatory elements. In late-stage progenitors, Ikzf4 re-localizes to bind target genes involved in Müller glia development and regulate their expression. Specifically, we show that Ikzf4 maintains Hes1 expression in differentiating cells using two Ikzf GGAA binding sites at the Hes1 promoter, thereby favouring Müller glia fate commitment. These results uncover a combinatorial role for Ikaros family members in nervous system development and provide mechanistic insights on how they temporally regulate cell fate output.

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