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 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 Interdependent regulation of stereotyped and stochastic photoreceptor fates in the fly eye

2019 ◽  
Author(s):  
Adam C. Miller ◽  
Elizabeth Urban ◽  
Eric L. Lyons ◽  
Tory G. Herman ◽  
Robert J. Johnston
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Gene Networks ◽  
Control Cell ◽  
Regulatory Mechanisms ◽  
Cell Fates ◽  
Feedback Mechanisms ◽  
Fate Specification ◽  
Gene Regulatory ◽  
Fly Eye

AbstractDiversification of neuronal subtypes often requires stochastic gene regulatory mechanisms. How stochastically expressed transcription factors interact with other regulators in gene networks to specify cell fates is poorly understood. The random mosaic of color-detecting R7 photoreceptor subtypes in Drosophila is controlled by the stochastic on/off expression of the transcription factor Spineless (Ss). In SsON R7s, Ss induces expression of Rhodopsin 4 (Rh4), whereas in SsOFF R7s, the absence of Ss allows expression of Rhodopsin 3 (Rh3). Here, we find that the transcription factor Runt, which is initially expressed in all R7s, activates expression of Spineless in a random subset of R7s. Later, as R7s develop, Ss negatively feeds back onto Runt to prevent repression of Rh4 and ensure proper fate specification. Together, stereotyped and stochastic regulatory inputs are integrated into feedforward and feedback mechanisms to control cell fate.

scholarly journals PAG-3, a Zn-finger transcription factor, determines neuroblast fate in C. elegans

Development ◽  
2002 ◽  
Vol 129 (7) ◽  
pp. 1763-1774 ◽  
Author(s):  
Scott Cameron ◽  
Scott G. Clark ◽  
Joan B. McDermott ◽  
Eric Aamodt ◽  
H. Robert Horvitz
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Daughter Cell ◽  
Cell Lineage ◽  
Blast Cell ◽  
Cell Fates ◽  
Zinc Finger Transcription Factor ◽  
C Elegans ◽  
Mother Cells

During Caenorhabditis elegans development, the patterns of cell divisions, cell fates and programmed cell deaths are reproducible from animal to animal. In a search for mutants with abnormal patterns of programmed cell deaths in the ventral nerve cord, we identified mutations in the gene pag-3, which encodes a zinc-finger transcription factor similar to the mammalian Gfi-1 and Drosophila Senseless proteins. In pag-3 mutants, specific neuroblasts express the pattern of divisions normally associated with their mother cells, producing with each reiteration an abnormal anterior daughter neuroblast and an extra posterior daughter cell that either terminally differentiates or undergoes programmed cell death, which accounts for the extra cell corpses seen in pag-3 mutants. In addition, some neurons do not adopt their normal fates in pag-3 mutants. The phenotype of pag-3 mutants and the expression pattern of the PAG-3 protein suggest that in some lineages pag-3 couples the determination of neuroblast cell fate to subsequent neuronal differentiation. We propose that pag-3 counterparts in other organisms determine blast cell identity and for this reason may lead to cell lineage defects and cell proliferation when mutated.

scholarly journals The prospero transcription factor is asymmetrically localized to the cell cortex during neuroblast mitosis in Drosophila

Development ◽  
1995 ◽  
Vol 121 (10) ◽  
pp. 3187-3195 ◽  
Author(s):  
E.P. Spana ◽  
C.Q. Doe
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Cell Fate ◽  
Daughter Cell ◽  
Cell Cortex ◽  
Cell Fates ◽  
Extrinsic Factors ◽  
Cortical Localization ◽  
Ganglion Mother Cell ◽  
Intrinsic And Extrinsic Factors

Both intrinsic and extrinsic factors are known to regulate sibling cell fate. Here we describe a novel mechanism for the asymmetric localization of a transcription factor to one daughter cell at mitosis. The Drosophila CNS develops from asymmetrically dividing neuroblasts, which give rise to a large neuroblast and a smaller ganglion mother cell (GMC). The prospero gene encodes a transcription factor necessary for proper GMC gene expression. We show that the prospero protein is synthesized in the neuroblast where it is localized to the F-actin cell cortex. At mitosis, prospero is asymmetrically localized to the budding GMC and excluded from the neuroblast. After cytokinesis, prospero is translocated from the GMC cortex into the nucleus. Asymmetric cortical localization of prospero in neuroblasts requires entry into mitosis; it does not depend on numb function. prospero is also observed in cortical crescents in dividing precursors of the peripheral nervous system and adult midgut. The asymmetric cortical localization of prospero at mitosis is a mechanism for rapidly establishing distinct sibling cell fates in the CNS and possibly other tissues.

Sibling cell fate in the Drosophila adult external sense organ lineage is specified by prospero function, which is regulated by Numb and Notch

Development ◽  
1999 ◽  
Vol 126 (10) ◽  
pp. 2083-2092 ◽  
Author(s):  
G.V. Reddy ◽  
V. Rodrigues
Keyword(s):  
Transcription Factor ◽  
Notch Signaling ◽  
Cell Fate ◽  
Sense Organ ◽  
Sensory Organ ◽  
Sensory Organs ◽  
Cell Fates ◽  
Homeodomain Transcription Factor ◽  
Intrinsic Signal ◽  
Sensory Organ Precursors

Specification of cell fate in the adult sensory organs is known to be dependent on intrinsic and extrinsic signals. We show that the homeodomain transcription factor Prospero (Pros) acts as an intrinsic signal for the specification of cell fates within the mechanosensory lineage. The sensory organ precursors divide to give rise to two secondary progenitors - PIIa and PIIb. Pros is expressed in PIIb, which gives rise to the neuron and thecogen cells. Loss of Pros function affects the identity of PIIb and neurons fail to differentiate. Pros misexpression is sufficient for the transformation of PIIa to PIIb fate. The expression of Pros in the normal PIIb cell appears to be regulated by Notch signaling.

scholarly journals Numb Proteins Specify Asymmetric Cell Fates via an Endocytosis- and Proteasome-Independent Pathway

2005 ◽  
Vol 25 (8) ◽  
pp. 2899-2909 ◽  
Author(s):  
Haiyan Tang ◽  
Santiago B. Rompani ◽  
Joshua B. Atkins ◽  
Yan Zhou ◽  
Thomas Osterwalder ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Cell Communication ◽  
Cell Fates ◽  
Binding Motifs ◽  
Protein Levels ◽  
Daughter Cells ◽  
Notch Protein ◽  
Evolutionarily Conserved ◽  
Asymmetric Divisions

ABSTRACT Numb proteins are evolutionarily conserved signaling molecules that make the daughter cells different after asymmetric divisions by segregating to only one daughter. They contain distinct binding motifs for α-adaptin (α-Ada) and proteins with Eps15 homology (EH) domains, which regulate endocytosis, and for E3 ubiquitin ligases, which target proteins for proteasome-mediated degradation. In Drosophila melanogaster, Numb acts by inhibiting Notch activity to cause a bias in Notch-mediated cell-cell communication. These findings have led to the hypothesis that Numb modulates Notch signaling by using endocytosis and proteasomes to directly reduce Notch protein levels at the cell surface. Here we show that two Drosophila EH proteins, Eps15 homologue 1 (EH1) and the dynamin-associated 160-kDa protein (Dap160), negatively regulate Notch signaling. However, neither elimination of the binding motifs for endocytic proteins nor simultaneous reduction of proteasome activity affects the activity of Numb proteins. Our findings indicate that an endocytosis- and proteasome-independent pathway may mediate Numb signaling in asymmetric cell fate specification.

scholarly journals Lung lineage transcription factor NKX2-1 epigenetically resolves opposing cell fates in vivo

2020 ◽  
Author(s):  
Danielle R. Little ◽  
Anne M. Lynch ◽  
Yun Yan ◽  
Haruhiko Akiyama ◽  
Shioko Kimura ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Dna Sequences ◽  
Cell Biology ◽  
Specific Binding ◽  
Genomic Analysis ◽  
Mouse Lung ◽  
Alveolar Type ◽  
Cell Fates

ABSTRACTDifferential use of identical DNA sequences leads to distinct tissue lineages and then multiple cell types within a lineage, an epigenetic process central to progenitor and stem cell biology. The associated genomic changes, especially in native tissues, remain insufficiently understood, and are hereby addressed in the mouse lung, where the same lineage transcription factor NKX2-1 promotes the diametrically opposed alveolar type 1 (AT1) and AT2 cell fates. We show that the cell-type-specific function of NKX2-1 is attributed to its differential chromatin binding that is acquired or retained during development in coordination with partner transcriptional factors. Loss of YAP/TAZ redirects NKX2-1 from its AT1-specific to AT2-specific binding sites, leading to transcriptionally exaggerated AT2 cells when deleted in progenitors or AT1-to-AT2 conversion when deleted after fate commitment. Nkx2-1 mutant AT1 and AT2 cells gain distinct accessible sites including those of the opposite fate while adopting the gastrointestinal fate, suggesting an epigenetic plasticity larger than a transcriptional one. Our genomic analysis of single or purified cells, coupled with precision genetics, provides an epigenetic roadmap of alveolar cell fate and potential, and introduces an experimental benchmark for unraveling the in vivo function of lineage transcription factors.

scholarly journals Phospho-signal flow from a pole-localized microdomain spatially patterns transcription factor activity

2017 ◽  
Author(s):  
Keren Lasker ◽  
Alex von Diezmann ◽  
Daniel G. Ahrens ◽  
Thomas H. Mann ◽  
W. E. Moerner ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Single Molecule ◽  
Transcriptional Activation ◽  
Intracellular Signaling ◽  
Caulobacter Crescentus ◽  
Transcriptional Profiling ◽  
Reaction Diffusion ◽  
Single Molecule Tracking ◽  
Daughter Cells

SUMMARYSelective recruitment and concentration of signaling proteins within membrane-less compartments is a ubiquitous mechanism for subcellular organization. However, little is known about how such dynamic recruitment patterns intracellular signaling and cellular development. Here, we combined transcriptional profiling, reaction-diffusion modeling, and single-molecule tracking to study signal exchange in and out of a microdomain at the cell pole of the asymmetrically dividing bacteriumCaulobacter crescentus.Our study revealed that the microdomain is selectively permeable, and that each protein in the signaling pathway that activates the cell fate transcription factor CtrA is sequestered and uniformly concentrated within the microdomain or its proximal membrane. Restricted rates of entry into and escape from the microdomain enhance phospho-signaling, leading to a sublinear gradient of CtrA~P along the long axis of the cell. The spatial patterning of CtrA~P creates a gradient of transcriptional activation that serves to prime asymmetric development of the two daughter cells.

scholarly journals Drosophila Notch receptor activity suppresses Hairless function during adult external sensory organ development.

Genetics ◽  
1995 ◽  
Vol 141 (4) ◽  
pp. 1491-1505
Author(s):  
D F Lyman ◽  
B Yedvobnick
Keyword(s):  
Cell Fate ◽  
Daughter Cell ◽  
Notch Receptor ◽  
Sensory Organ ◽  
Cell Fates ◽  
Gain Of Function ◽  
Over Expression ◽  
Cell Fate Decisions ◽  
Synergistic Enhancement ◽  
Conditional Expression

Abstract The neurogenic Notch locus of Drosophila encodes a receptor necessary for cell fate decisions within equivalence groups, such as proneural clusters. Specification of alternate fates within clusters results from inhibitory communication among cells having comparable neural fate potential. Genetically, Hairless (H) acts as an antagonist of most neurogenic genes and may insulate neural precursor cells from inhibition. H function is required for commitment to the bristle sensory organ precursor (SOP) cell fate and for daughter cell fates. Using Notch gain-of-function alleles and conditional expression of an activated Notch transgene, we show that enhanced signaling produces H-like loss-of-function phenotypes by suppressing bristle SOP cell specification or by causing an H-like transformation of sensillum daughter cell fates. Furthermore, adults carrying Notch gain of function and H alleles exhibit synergistic enhancement of mutant phenotypes. Over-expression of an H+ transgene product suppressed virtually all phenotypes generated by Notch gain-of-function genotypes. Phenotypes resulting from over-expression of the H+ transgene were blocked by the Notch gain-of-function products, indicating a balance between Notch and H activity. The results suggest that H insulates SOP cells from inhibition and indicate that H activity is suppressed by Notch signaling.

Sign in / Sign up

Export Citation Format

Share Document