scholarly journals The WT1-like transcription factor Klumpfuss maintains lineage commitment of enterocyte progenitors in the Drosophila intestine

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Jerome Korzelius ◽  
Sina Azami ◽  
Tal Ronnen-Oron ◽  
Philipp Koch ◽  
Maik Baldauf ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
Cell Fate ◽  
Progenitor Cell ◽  
Lineage Commitment ◽  
Proneural Gene ◽  
Cell Lineages ◽  
Daughter Cells ◽  
Mechanistic Insight ◽  
Insight Into

Abstract In adult epithelial stem cell lineages, the precise differentiation of daughter cells is critical to maintain tissue homeostasis. Notch signaling controls the choice between absorptive and entero-endocrine cell differentiation in both the mammalian small intestine and the Drosophila midgut, yet how Notch promotes lineage restriction remains unclear. Here, we describe a role for the transcription factor Klumpfuss (Klu) in restricting the fate of enteroblasts (EBs) in the Drosophila intestine. Klu is induced in Notch-positive EBs and its activity restricts cell fate towards the enterocyte (EC) lineage. Transcriptomics and DamID profiling show that Klu suppresses enteroendocrine (EE) fate by repressing the action of the proneural gene Scute, which is essential for EE differentiation. Loss of Klu results in differentiation of EBs into EE cells. Our findings provide mechanistic insight into how lineage commitment in progenitor cell differentiation can be ensured downstream of initial specification cues.

scholarly journals The BTB-ZF transcription factor Tramtrack69 shapes neural cell lineages by coordinating cell proliferation and cell fate

2018 ◽  
Author(s):  
Françoise Simon ◽  
Anne Ramat ◽  
Sophie Louvet-Vallée ◽  
Jérôme Lacoste ◽  
Angélique Burg ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Transcription Factor ◽  
Cell Fate ◽  
Progenitor Cell ◽  
Molecular Mechanisms ◽  
Neural Cell ◽  
Cell Cycle Exit ◽  
Cell Lineages ◽  
Accessory Cells

AbstractCell diversity in multicellular organisms relies on coordination between cell proliferation and the acquisition of cell identity. The equilibrium between these two processes is essential to assure the correct number of determined cells at a given time at a given place. Here, we show that Tramtrack-69 (Ttk69, a BTB-ZF transcription factor ortholog of the human PLZF factor) plays an essential role in controlling this balance. In theDrosophilabristle cell lineage, producing the external sensory organs composed by a neuron and accessory cells, we show thatttk69loss of function leads to supplementary neural-type cells at the expense of accessory cells. Our data indicate that Ttk69 (1) promotes cell-cycle exit of newborn terminal cells by downregulatingcycE, the principal cyclin involved in S-phase entry and (2) regulates cell fate acquisition and terminal differentiation by downregulating the expression ofhamletand upregulating that ofSuppressor of Hairless, two transcription factors involved in neural-fate acquisition and accessory-cell differentiation, respectively. Thus, Ttk69 plays a central role in shaping neural cell lineages by integrating molecular mechanisms that regulate progenitor cell-cycle exit and cell-fate commitment.Summary statementTramtrack-69, a transcription factor orthologous to the human tumor-suppressor PLZF, plays a central role in precursor cell lineages by integrating molecular mechanisms that regulate progenitor cell-cycle exit and cell-fate determination.

scholarly journals The EGL-13 SOX Domain Transcription Factor Affects the Uterine Cell Lineages in Caenorhabditis elegans

Genetics ◽  
2003 ◽  
Vol 165 (3) ◽  
pp. 1623-1628
Author(s):  
Hediye Nese Cinar ◽  
Keri L Richards ◽  
Kavita S Oommen ◽  
Anna P Newman
Keyword(s):  
Transcription Factor ◽  
Cell Division ◽  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Cell Lineages

Abstract We isolated egl-13 mutants in which the cells of the Caenorhabditis elegans uterus initially appeared to develop normally but then underwent an extra round of cell division. The data suggest that egl-13 is required for maintenance of the cell fate.

scholarly journals Shaping of Drosophila Neural Cell Lineages Through Coordination of Cell Proliferation and Cell Fate by the BTB-ZF Transcription Factor Tramtrack-69

Genetics ◽  
2019 ◽  
Vol 212 (3) ◽  
pp. 773-788
Author(s):  
Françoise Simon ◽  
Anne Ramat ◽  
Sophie Louvet-Vallée ◽  
Jérôme Lacoste ◽  
Angélique Burg ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Transcription Factor ◽  
Cell Fate ◽  
Zinc Finger ◽  
Molecular Mechanisms ◽  
Neural Cell ◽  
Cell Cycle Exit ◽  
Cell Lineages ◽  
Accessory Cells

Cell diversity in multicellular organisms relies on coordination between cell proliferation and the acquisition of cell identity. The equilibrium between these two processes is essential to assure the correct number of determined cells at a given time at a given place. Using genetic approaches and correlative microscopy, we show that Tramtrack-69 (Ttk69, a Broad-complex, Tramtrack and Bric-à-brac - Zinc Finger (BTB-ZF) transcription factor ortholog of the human promyelocytic leukemia zinc finger factor) plays an essential role in controlling this balance. In the Drosophila bristle cell lineage, which produces the external sensory organs composed by a neuron and accessory cells, we show that ttk69 loss-of-function leads to supplementary neural-type cells at the expense of accessory cells. Our data indicate that Ttk69 (1) promotes cell cycle exit of newborn terminal cells by downregulating CycE, the principal cyclin involved in S-phase entry, and (2) regulates cell-fate acquisition and terminal differentiation, by downregulating the expression of hamlet and upregulating that of Suppressor of Hairless, two transcription factors involved in neural-fate acquisition and accessory cell differentiation, respectively. Thus, Ttk69 plays a central role in shaping neural cell lineages by integrating molecular mechanisms that regulate progenitor cell cycle exit and cell-fate commitment.

scholarly journals NUMB regulates the endocytosis and activity of the anaplastic lymphoma kinase in an isoform-specific manner

2019 ◽  
Vol 11 (11) ◽  
pp. 994-1005 ◽  
Author(s):  
Ran Wei ◽  
Xuguang Liu ◽  
Courtney Voss ◽  
Wentao Qin ◽  
Lina Dagnino ◽  
...  
Keyword(s):  
Cell Fate ◽  
Receptor Tyrosine Kinase ◽  
Anaplastic Lymphoma Kinase ◽  
Degradation Pathway ◽  
Anaplastic Lymphoma ◽  
Mechanistic Insight ◽  
Evolutionarily Conserved ◽  
Specific Manner ◽  
Insight Into

Abstract NUMB is an evolutionarily conserved protein that plays an important role in cell adhesion, migration, polarity, and cell fate determination. It has also been shown to play a role in the pathogenesis of certain cancers, although it remains controversial whether NUMB functions as an oncoprotein or tumor suppressor. Here, we show that NUMB binds to anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase aberrantly activated in several forms of cancer, and this interaction regulates the endocytosis and activity of ALK. Intriguingly, the function of the NUMB–ALK interaction is isoform-dependent. While both p66-NUMB and p72-NUMB isoforms are capable of mediating the endocytosis of ALK, the former directs ALK to the lysosomal degradation pathway, thus decreasing the overall ALK level and the downstream MAP kinase signal. In contrast, the p72-NUMB isoform promotes ALK recycling back to the plasma membrane, thereby maintaining the kinase in its active state. Our work sheds light on the controversial role of different isoforms of NUMB in tumorigenesis and provides mechanistic insight into ALK regulation.

scholarly journals Reconstruction of rat retinal progenitor cell lineages in vitro reveals a surprising degree of stochasticity in cell fate decisions

Development ◽  
2010 ◽  
Vol 138 (2) ◽  
pp. 227-235 ◽  
Author(s):  
F. L. A. F. Gomes ◽  
G. Zhang ◽  
F. Carbonell ◽  
J. A. Correa ◽  
W. A. Harris ◽  
...  
Keyword(s):  
Cell Fate ◽  
Progenitor Cell ◽  
Retinal Progenitor Cell ◽  
Cell Fate Decisions ◽  
Cell Lineages ◽  
Retinal Progenitor

scholarly journals The WT1-like transcription factor Klumpfuss maintains lineage commitment in the intestine

2019 ◽  
Author(s):  
Jerome Korzelius ◽  
Tal Ronnen-Oron ◽  
Maik Baldauf ◽  
Elke Meier ◽  
Pedro Sousa-Victor ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Feedback Loop ◽  
Common Mechanism ◽  
Cell Fates ◽  
Daughter Cells ◽  
Transient Activation ◽  
Transient Activity ◽  
Temporal Restriction ◽  
High Degree

AbstractStem cell (SC) lineages in barrier epithelia exhibit a high degree of plasticity. Mechanisms that govern the precise specification of SC daughter cells during regenerative episodes are therefore critical to maintain homeostasis. One such common mechanism is the transient activation of the Notch (N) signaling pathway. N controls the choice between absorptive and entero-endocrine cell fates in both the mammalian small intestine and theDrosophilamidgut, yet how precisely N signaling promotes lineage restriction in progenitor cells remains unclear. Here, we describe a role for the WT1-like transcription factor Klumpfuss (Klu) in restricting the fate ofDrosophilaenteroblasts (EBs) downstream of N activation. Klu is transiently induced in Notch-positive EBs and its transient activity restricts cell fate towards the enterocyte (EC) lineage. Transcriptomics and DamID profiling show that Klu suppresses enteroendocrine (EE) cell fates by repressing E(Spl)m8-HLH and Phyllopod, both negative regulators of the proneural gene Scute, which is essential for EE differentiation. At the same time, Klu suppresses cell cycle genes, committing EBs to differentiation. Klu-mediated repression of its own transcription further sets up a negative feedback loop that ensures temporal restriction of Klu-mediated gene regulation, and is essential for subsequent differentiation of ECs. Our findings define a transient cell state in which EC lineage restriction is cemented, and establish a hierarchy of transcriptional programs critical in executing a differentiation program downstream of initial induction events governed by N signaling.

scholarly journals The Spatiotemporal Expression of Notch1 and Numb and Their Functional Interaction during Cardiac Morphogenesis

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2192
Author(s):  
Lianjie Miao ◽  
Yangyang Lu ◽  
Anika Nusrat ◽  
Hala Y. Abdelnasser ◽  
Sayantap Datta ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Cell Fate ◽  
Progenitor Cell ◽  
Structural Defects ◽  
Asymmetric Distribution ◽  
Cardiomyocyte Proliferation ◽  
Double Knockout ◽  
Cardiac Morphogenesis ◽  
Cardiac Progenitor Cell ◽  
Notch Activation

Numb family proteins (NFPs), including Numb and Numblike (Numbl), are commonly known for their role as cell fate determinants for multiple types of progenitor cells, mainly due to their function as Notch inhibitors. Previous studies have shown that myocardial NFP double knockout (MDKO) hearts display an up-regulated Notch activation and various defects in cardiac progenitor cell differentiation and cardiac morphogenesis. Whether enhanced Notch activation causes these defects in MDKO is not fully clear. To answer the question, we examined the spatiotemporal patterns of Notch1 expression, Notch activation, and Numb expression in the murine embryonic hearts using multiple approaches including RNAScope, and Numb and Notch reporter mouse lines. To further interrogate the interaction between NFPs and Notch signaling activation, we deleted both Notch1 or RBPJk alleles in the MDKO. We examined and compared the phenotypes of Notch1 knockout, NFPs double knockout, Notch1; Numb; Numbl and RBPJk; Numb; Numbl triple knockouts. Our study showed that Notch1 is expressed and activated in the myocardium at several stages, and Numb is enriched in the epicardium and did not show the asymmetric distribution in the myocardium. Cardiac-specific Notch1 deletion causes multiple structural defects and embryonic lethality. Notch1 or RBPJk deletion in MDKO did not rescue the structural defects in the MDKO but partially rescued the defects of cardiac progenitor cell differentiation, cardiomyocyte proliferation, and trabecular morphogenesis. Our study concludes that NFPs regulate progenitor cell differentiation, cardiomyocyte proliferation, and trabecular morphogenesis partially through Notch1 and play more roles than inhibiting Notch1 signaling during cardiac morphogenesis.

The Ordered Expression of Transcription Factors Directs Hierarchical Lineage Specification of Eosinophils, Basophils and Mast Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 224-224
Author(s):  
Hiromi Iwasaki ◽  
Yojiro Arinobu ◽  
Shin-ichi Mizuno ◽  
Hirokazu Shigematsu ◽  
Kiyoshi Takatsu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Mast Cell ◽  
Cell Fate ◽  
Gene Expression Analysis ◽  
Lineage Specification ◽  
Retroviral Transduction ◽  
Cell Lineages ◽  
Stem And Progenitor Cells ◽  
Eosinophil Colonies

Abstract Here we show that eosinophil progenitors (EoPs) and basophil/mast cell progenitors (BMCPs) are prospectively isolatable in normal hematopoiesis, and that their lineage decisions are regulated principally by GATA-2 and C/EBPα. These progenitors were isolated downstream of granulocyte/monocyte progenitors (GMPs), and BMCPs further generated monopotent basophil progenitors (BaPs) and mast cell progenitors (MCPs). Gene expression analysis showed that neither GATA-1 nor GATA-2 was expressed in GMPs, whereas both of them were upregulated in EoPs, BMCPs, BaPs and MCPs. Importantly, C/EBPα was expressed in EoPs and BaPs as well as GMPs, but was downregulated in BMCPs and MCPs. We have reported that GATA-1 is critical primarily for megakaryocyte/erythrocyte commitment or conversion of stem and progenitor cells. We therefore focused on GATA-2 and C/EBPα functions in this study. Since both EoPs and BaPs co-expressed GATA-2 and C/EBPα while GMPs expressed only C/EBPα, we first transduced GATA-2 into GMPs via a GFP-tagged retrovirus. Strikingly, all GATA-2+ GMPs gave rise to pure eosinophil colonies but not basophil colonies, indicating that enforced GATA-2 can instruct GMPs to become EoPs. Next, since BMCPs only expressed GATA-2 but not C/EBPα, we maintained the expression of C/EBPα in GMPs by retroviral transduction. Interestingly, the sustained expression of C/EBPα blocked basophil/mast cell differentiation from GMPs, indicating that C/EBPα downregulation is required for GMPs to choose the basophil/mast cell fate. As a reciprocal experiment, we conditionally disrupted C/EBPα gene at the level of GMPs by retrovirally transducing Cre gene into GMPs purified from mice in which C/EBPα gene is flanked by loxP sequences (floxed: F). The frequency of mast cell read-out from C/EBPα-disrupted GMPs was 5-fold higher than that from C/EBPα F/F (Cre−) GMPs. C/EBPα-disrupted GMPs, however, did not give rise to BaPs. Furthermore, MCPs transduced with C/EBPα were converted into BaPs. Thus, C/EBPα is required to be reactivated during transition from BMCPs to BaPs. We further tested their interplay in specification of these lineages by using common lymphoid progenitors (CLPs), which do not express GATA-2 or C/EBPα. We enforced the expression of each transcription factor in CLPs in different orders by using the two-step retroviral transduction system. Interestingly, C/EBPα transduction reprogrammed CLPs into GM lineages, and subsequently-transduced GATA-2 instructed C/EBPα + CLPs to select the eosinophil fate. Next, we switched the order of transduction. Strikingly, GATA-2 transduction converted CLPs into BMCPs, and subsequently-transduced C/EBPα specified GATA-2+ CLPs to become BaPs. Thus, at the branchpoint for EoPs and BMCPs, GATA-2 upregulation instructed EoP development if C/EBPα was present, whereas it instructed BMCP development if C/EBPα was absent. After the BMCP stage, C/EBPα had to remain suppressed for MCP development, whereas BaPs developed by C/EBPα reactivation. These data collectively suggest that the order of expression of GATA-2 and C/EBPα is critical for their interplay to selectively activate developmental programs for the eosinophil, the basophil and the mast cell lineages.

scholarly journals A universal transportin protein drives stochastic choice of olfactory neurons via specific nuclear import of a sox-2-activating factor

2019 ◽  
Vol 116 (50) ◽  
pp. 25137-25146
Author(s):  
Amel Alqadah ◽  
Yi-Wen Hsieh ◽  
Rui Xiong ◽  
Bluma J. Lesch ◽  
Chieh Chang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Potassium Channels ◽  
Cell Fate ◽  
Nuclear Import ◽  
Neuronal Cell ◽  
High Mobility ◽  
Olfactory Neuron ◽  
Loss Of Function ◽  
Stochastic Choice ◽  
Insight Into

Stochastic neuronal cell fate choice involving notch-independent mechanisms is a poorly understood biological process. The Caenorhabditis elegans AWC olfactory neuron pair asymmetrically differentiates into the default AWCOFF and induced AWCON subtypes in a stochastic manner. Stochastic choice of the AWCON subtype is established using gap junctions and SLO BK potassium channels to repress a calcium-activated protein kinase pathway. However, it is unknown how the potassium channel-repressed calcium signaling is translated into the induction of the AWCON subtype. Here, we identify a detailed working mechanism of how the homeodomain-like transcription factor NSY-7, previously described as a repressor in the maintenance of AWC asymmetry, couples SLO BK potassium channels to transactivation of sox-2 expression for the induction of the AWCON subtype through the identification of a unique imb-2 (transportin 1) allele. imb-2 loss-of-function mutants are not viable; however, we identify a viable imb-2 allele from an unbiased forward genetic screen that reveals a specific role of imb-2 in AWC olfactory neuron asymmetry. IMB-2 specifically drives nuclear import of NSY-7 within AWC neurons to transactivate the expression of the high mobility group (HMG)-box transcription factor SOX-2 for the specification of the AWCON subtype. This study provides mechanistic insight into how NSY-7 couples SLO BK potassium channels to transactivation of sox-2 expression for the induction of the AWCON subtype. Our findings also provide structure-function insight into a conserved amino acid residue of transportins in brain development and suggest its dysfunction may lead to human neurological disorders.

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