scholarly journals Coregulation of anterior and posterior mesendodermal development by a hairy-related transcriptional repressor

2000 ◽  
Vol 14 (13) ◽  
pp. 1664-1677 ◽  
Author(s):  
Laure Bally-Cuif ◽  
Carole Goutel ◽  
Marion Wassef ◽  
Wolfgang Wurst ◽  
Frédéric Rosa
Keyword(s):  
Cell Fate ◽  
Critical Role ◽  
Transcriptional Repressor ◽  
Cell Interaction ◽  
Wild Type ◽  
Cell Fate Decisions ◽  
Interaction Processes ◽  
Mutant Forms ◽  
Local Release ◽  
Enhancer Of Split

During embryonic development in vertebrates, the endoderm becomes patterned along the anteroposterior axis to produce distinct derivatives. How this regulation is controlled is not well understood. We report that the zebrafish hairy/enhancer of split [E(spl)]-related gene her5 plays a critical role in this process. At gastrulation, following endoderm induction and further cell interaction processes including a local release of Notch/Delta signaling, her5 expression is progressively excluded from the presumptive anterior- and posteriormost mesendodermal territories to become restricted to an adjacent subpopulation of dorsal endodermal precursors. Ectopic misexpressions of wild-type and mutant forms of her5 reveal that her5functions primarily within the endodermal/endmost mesendodermal germ layer to inhibit cell participation to the endmost-fated mesendoderm. In this process, her5 acts as an active transcriptional repressor. These features are strikingly reminiscent of the function of Drosophila Hairy/E(spl) factors in cell fate decisions. Our results provide the first model for vertebrate endoderm patterning where an early regulatory step at gastrulation, mediated by her5 controls cell contribution jointly to the anterior- and posteriormost mesendodermal regions.

Role of Notch and achaete-scute complex in the expression of Enhancer of split bHLH proteins

Development ◽  
1995 ◽  
Vol 121 (11) ◽  
pp. 3745-3752 ◽  
Author(s):  
V. Jennings ◽  
J. de Celis ◽  
C. Delidakis ◽  
A. Preiss ◽  
S. Bray
Keyword(s):  
Cell Fate ◽  
Notch Pathway ◽  
Interaction Mechanism ◽  
Cell Interaction ◽  
Precursor Cell ◽  
Notch Receptor ◽  
Sensory Organ ◽  
Cell Fate Decisions ◽  
Sensory Organ Precursor ◽  
Enhancer Of Split

The proteins encoded by Notch and the Enhancer of split complex are components of a cell-cell interaction mechanism which is important in many cell fate decisions throughout development. One such decision is the formation of the sensory organ precursor cell during the development of the peripheral nervous system in Drosophila. Cells acquire the potential to be neural through the expression of the proneural genes, and the Notch pathway is required to limit neural fate to a single cell from a proneural cluster. However, despite extensive analysis, the precise pathways linking the proneural with Notch and Enhancer of split gene functions remain obscure. For example, it has been suggested that achaete-scute complex proteins directly activate Enhancer of split genes leaving the action of Notch in the pathway unclear. Using monoclonal antibodies that recognise products of the Enhancer of split complex, we show that these proteins accumulate in the cells surrounding the developing sensory organ precursor cell and that their expression is dependent on the activity of Notch and does not directly correlate with expression of Achaete. We further clarify the pathway by showing that ubiquitous expression of an activated Notch receptor leads to widespread accumulation of Enhancer of split proteins even in the absence of achaete-scute complex proteins. Thus Enhancer of split protein expression in response to Notch activity does not require achaete-scute complex proteins.

scholarly journals Regulation of the cognitive aging process by the transcriptional repressor RP58

2021 ◽  
Author(s):  
Tomoko Tanaka ◽  
Shinobu Hirai ◽  
Hiroyuki Manabe ◽  
Kentaro Endo ◽  
Hiroko Shimbo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Knockout Mice ◽  
Cognitive Aging ◽  
Critical Role ◽  
Harmful Effect ◽  
Transcriptional Repressor ◽  
Repair Pathway ◽  
Wild Type

Aging involves a decline in physiology which is a natural event in all living organisms. An accumulation of DNA damage contributes to the progression of aging. DNA is continually damaged by exogenous sources and endogenous sources. If the DNA repair pathway operates normally, DNA damage is not life threatening. However, impairments of the DNA repair pathway may result in an accumulation of DNA damage, which has a harmful effect on health and causes an onset of pathology. RP58, a zinc-finger transcriptional repressor, plays a critical role in cerebral cortex formation. Recently, it has been reported that the expression level of RP58 decreases in the aged human cortex. Furthermore, the role of RP58 in DNA damage is inferred by the involvement of DNMT3, which acts as a co-repressor for RP58, in DNA damage. Therefore, RP58 may play a crucial role in the DNA damage associated with aging. In the present study, we investigated the role of RP58 in aging. We used RP58 hetero-knockout and wild-type mice in adolescence, adulthood, or old age. We performed immunohistochemistry to determine whether microglia and DNA damage markers responded to the decline in RP58 levels. Furthermore, we performed an object location test to measure cognitive function, which decline with age. We found that the wild-type mice showed an increase in single-stranded DNA and gamma-H2AX foci. These results indicate an increase in DNA damage or dysfunction of DNA repair mechanisms in the hippocampus as age-related changes. Furthermore, we found that, with advancing age, both the wild-type and hetero-knockout mice showed an impairment of spatial memory for the object and increase in reactive microglia in the hippocampus. However, the RP58 hetero-knockout mice showed these symptoms earlier than the wild-type mice did. These results suggest that a decline in RP58 level may lead to the progression of aging.

scholarly journals A novel Axin2 knock-in mouse model for visualization and lineage tracing of WNT/CTNNB1 responsive cells

2020 ◽  
Author(s):  
Anoeska Agatha Alida van de Moosdijk ◽  
Yorick Bernardus Cornelis van de Grift ◽  
Saskia Madelon Ada de Man ◽  
Amber Lisanne Zeeman ◽  
Renée van Amerongen
Keyword(s):  
Cell Fate ◽  
Mouse Strain ◽  
Critical Role ◽  
Lineage Tracing ◽  
Fluorescent Reporter ◽  
Cell Fate Decisions ◽  
Stem Cell Maintenance ◽  
Signaling Dynamics ◽  
Before And After

AbstractWnt signal transduction controls tissue morphogenesis, maintenance and regeneration in all multicellular animals. In mammals, the WNT/CTNNB1 (Wnt/β-catenin) pathway controls cell proliferation and cell fate decisions before and after birth. It plays a critical role at multiple stages of embryonic development, but also governs stem cell maintenance and homeostasis in adult tissues. However, it remains challenging to monitor endogenous WNT/CTNNB1 signaling dynamics in vivo. Here we report the generation and characterization of a new knock-in mouse strain that doubles as a fluorescent reporter and lineage tracing driver for WNT/CTNNB1 responsive cells. We introduced a multi-cistronic targeting cassette at the 3’ end of the universal WNT/CTNNB1 target gene Axin2. The resulting knock-in allele expresses a bright fluorescent reporter (3xNLS-SGFP2) and a doxycycline-inducible driver for lineage tracing (rtTA3). We show that the Axin2P2A-rtTA3-T2A-3xNLS-SGFP2 strain labels WNT/CTNNB1 cells at multiple anatomical sites during different stages of embryonic and postnatal development. It faithfully reports the subtle and dynamic changes in physiological WNT/CTNNB1 signaling activity that occur in vivo. We expect this mouse strain to be a useful resource for biologists who want to track and trace the location and developmental fate of WNT/CTNNB1 responsive stem cells in different contexts.Abstract Figure

scholarly journals Laminin β2 Chain Regulates Cell Cycle Dynamics in the Developing Retina

2022 ◽  
Vol 9 ◽  
Author(s):  
Dmitri Serjanov ◽  
Galina Bachay ◽  
Dale D. Hunter ◽  
William J. Brunken
Keyword(s):  
Cell Cycle ◽  
Cell Fate ◽  
Critical Role ◽  
Laminin Receptor ◽  
Cell Cycle Exit ◽  
Cell Fate Decisions ◽  
M Phase ◽  
Cell Cycle Dynamics ◽  
Laminin Β2

Vertebrate retinal development follows a highly stereotyped pattern, in which the retinal progenitor cells (RPCs) give rise to all retinal types in a conserved temporal sequence. Ensuring the proper control over RPC cell cycle exit and re-entry is, therefore, crucially important for the generation of properly functioning retina. In this study, we demonstrate that laminins, indispensible ECM components, at the retinal surface, regulate the mechanisms determining whether RPCs generate proliferative or post-mitotic progeny. In vivo deletion of laminin β2 in mice resulted in disturbing the RPC cell cycle dynamics, and premature cell cycle exit. Specifically, the RPC S-phase is shortened, with increased numbers of cells present in its late stages. This is followed by an accelerated G2-phase, leading to faster M-phase entry. Finally, the M-phase is extended, with RPCs dwelling longer in prophase. Addition of exogenous β2-containing laminins to laminin β2-deficient retinal explants restored the appropriate RPC cell cycle dynamics, as well as S and M-phase progression, leading to proper cell cycle re-entry. Moreover, we show that disruption of dystroglycan, a laminin receptor, phenocopies the laminin β2 deletion cell cycle phenotype. Together, our findings suggest that dystroglycan-mediated ECM signaling plays a critical role in regulating the RPC cell cycle dynamics, and the ensuing cell fate decisions.

scholarly journals Mechanoregulation of YAP and TAZ in Cellular Homeostasis and Disease Progression

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaomin Cai ◽  
Kuei-Chun Wang ◽  
Zhipeng Meng
Keyword(s):  
Cell Fate ◽  
Vascular System ◽  
Tissue Injury ◽  
Hippo Pathway ◽  
Critical Role ◽  
Cell Interaction ◽  
Tissue Growth ◽  
Cyclic Stretch ◽  
Mechanical Stimuli ◽  
Hemodynamic Forces

Biophysical cues, such as mechanical properties, play a critical role in tissue growth and homeostasis. During organ development and tissue injury repair, compressive and tensional forces generated by cell-extracellular matrix or cell-cell interaction are key factors for cell fate determination. In the vascular system, hemodynamic forces, shear stress, and cyclic stretch modulate vascular cell phenotypes and susceptibility to atherosclerosis. Despite that emerging efforts have been made to investigate how mechanotransduction is involved in tuning cell and tissue functions in various contexts, the regulatory mechanisms remain largely unknown. One of the challenges is to understand the signaling cascades that transmit mechanical cues from the plasma membrane to the cytoplasm and then to the nuclei to generate mechanoresponsive transcriptomes. YAP and its homolog TAZ, the Hippo pathway effectors, have been identified as key mechanotransducers that sense mechanical stimuli and relay the signals to control transcriptional programs for cell proliferation, differentiation, and transformation. However, the upstream mechanosensors for YAP/TAZ signaling and downstream transcriptome responses following YAP/TAZ activation or repression have not been well characterized. Moreover, the mechanoregulation of YAP/TAZ in literature is highly context-dependent. In this review, we summarize the biomechanical cues in the tissue microenvironment and provide an update on the roles of YAP/TAZ in mechanotransduction in various physiological and pathological conditions.

scholarly journals Proximity biotinylation identifies a set of conformation-specific interactions between Merlin and cell junction proteins

2019 ◽  
Vol 12 (578) ◽  
pp. eaau8749 ◽  
Author(s):  
Robert F. Hennigan ◽  
Jonathan S. Fletcher ◽  
Steven Guard ◽  
Nancy Ratner
Keyword(s):  
Tumor Suppressor ◽  
P53 Protein ◽  
Critical Role ◽  
Focal Adhesions ◽  
Neurofibromatosis Type ◽  
Cell Junction ◽  
Neoplastic Disease ◽  
Wild Type ◽  
Closed Conformation ◽  
Mutant Forms

Neurofibromatosis type 2 is an inherited, neoplastic disease associated with schwannomas, meningiomas, and ependymomas and that is caused by inactivation of the tumor suppressor gene NF2. The NF2 gene product, Merlin, has no intrinsic catalytic activity; its tumor suppressor function is mediated through the proteins with which it interacts. We used proximity biotinylation followed by mass spectrometry and direct binding assays to identify proteins that associated with wild-type and various mutant forms of Merlin in immortalized Schwann cells. We defined a set of 52 proteins in close proximity to wild-type Merlin. Most of the Merlin-proximal proteins were components of cell junctional signaling complexes, suggesting that additional potential interaction partners may exist in adherens junctions, tight junctions, and focal adhesions. With mutant forms of Merlin that cannot bind to phosphatidylinositol 4,5-bisphosphate (PIP2) or that constitutively adopt a closed conformation, we confirmed a critical role for PIP2 binding in Merlin function and identified a large cohort of proteins that specifically interacted with Merlin in the closed conformation. Among these proteins, we identified a previously unreported Merlin-binding protein, apoptosis-stimulated p53 protein 2 (ASPP2, also called Tp53bp2), that bound to closed-conformation Merlin predominately through the FERM domain. Our results demonstrate that Merlin is a component of cell junctional mechanosensing complexes and defines a specific set of proteins through which it acts.

Promoting notochord fate and repressing muscle development in zebrafish axial mesoderm

Development ◽  
1998 ◽  
Vol 125 (8) ◽  
pp. 1397-1406 ◽  
Author(s):  
S.L. Amacher ◽  
C.B. Kimmel
Keyword(s):  
Cell Fate ◽  
Double Mutant ◽  
Muscle Development ◽  
Genetic Interaction ◽  
Embryonic Cells ◽  
Wild Type ◽  
Environmental Signals ◽  
Cell Fate Decisions ◽  
Muscle Genes ◽  
Midline Cells

Cell fate decisions in early embryonic cells are controlled by interactions among developmental regulatory genes. Zebrafish floating head mutants lack a notochord; instead, muscle forms under the neural tube. As shown previously, axial mesoderm in floating head mutant gastrulae fails to maintain expression of notochord genes and instead expresses muscle genes. Zebrafish spadetail mutant gastrulae have a nearly opposite phenotype; notochord markers are expressed in a wider domain than in wild-type embryos and muscle marker expression is absent. We examined whether these two phenotypes revealed an antagonistic genetic interaction by constructing the double mutant. Muscle does not form in the spadetail;floating head double mutant midline, indicating that spadetail function is required for floating head mutant axial mesoderm to transfate to muscle. Instead, the midline of spadetail;floating head double mutants is greatly restored compared to that of floating head mutants; the floor plate is almost complete and an anterior notochord develops. In addition, we find that floating head mutant cells can make both anterior and posterior notochord when transplanted into a wild-type host, showing that enviromental signals can override the predisposition of floating head mutant midline cells to make muscle. Taken together, these results suggest that repression of spadetail function by floating head is critical to promote notochord fate and prevent midline muscle development, and that cells can be recruited to the notochord by environmental signals.

scholarly journals Expression of an activated rasD gene changes cell fate decisions during Dictyostelium development.

1997 ◽  
Vol 8 (2) ◽  
pp. 303-312 ◽  
Author(s):  
S A Louis ◽  
G B Spiegelman ◽  
G Weeks
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Cell Mass ◽  
Cell Formation ◽  
Specific Gene ◽  
Wild Type ◽  
Multicellular Development ◽  
Cell Fate Decisions ◽  
Prespore Cell

It has been previously demonstrated that the expression of an activated rasD gene in wild-type Dictyostelium cells results in formation of aggregates with multitips, instead of the normal single tips, and a block in further development. In an attempt to better understand the role of activated RasD development, we examined cell-type-specific gene expression in a strain stably expressing high levels of RasD[G12T]. We found that the expression of prestalk cell-specific genes ecmA and tagB was markedly enhanced, whereas the expression of the prespore cell-specific gene cotC was reduced to very low levels. When the fate of cells in the multitipped aggregate was monitored with an ecmA/lacZ fusion, it appeared that most of the cells eventually adopted prestalk gene expression characteristics. When mixtures of the [G12T]rasD cells and Ax3 cells were induced to differentiate, chimeric pseudoplasmodia were not formed. Thus, although the [G12T]rasD transformant had a marked propensity to form prestalk cells, it could not supply the prestalk cell population when mixed with wild-type cells. Both stalk and spore cell formation occurred in low cell density monolayers of the [G12T]rasD strain, suggesting that at least part of the inhibition of stalk and spore formation during multicellular development involved inhibitory cell interactions within the cell mass. Models for the possible role of rasD in development are discussed.

Constitutively active Notch4 promotes early human hematopoietic progenitor cell maintenance while inhibiting differentiation and causes lymphoid abnormalities in vivo

Blood ◽  
2004 ◽  
Vol 104 (8) ◽  
pp. 2315-2322 ◽  
Author(s):  
Suzanne M. Vercauteren ◽  
Heather J. Sutherland
Keyword(s):  
Stem Cells ◽  
T Cell ◽  
Cell Fate ◽  
Fluorescent Protein ◽  
Critical Role ◽  
Cell Activity ◽  
Hematopoietic Progenitor Cell ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Constitutively Active

Abstract Notch transmembrane receptors are known to play a critical role in cell-fate decisions, with Notch1 shown to enhance self-renewal of hematopoietic stem cells and cause T-cell leukemia. Four Notch receptors exist, and the extent of redundancy and overlap in their function is unknown. Notch4 is structurally distinct from Notch1 through Notch3 and has not been extensively studied in hematopoiesis. By polymerase chain reaction (PCR) we find Notch4 transcript expression in human marrow cells and in both CD34+ and CD34– populations. When constitutively active Notch1 or Notch4 was overexpressed in normal human marrow or cord cells, we found reduced colony-forming and short-term proliferative ability while the primitive progenitor content of myeloid long-term cultures was significantly increased. Notch4–intracellular domain (Notch4-IC)–transduced cord cells transplanted into β2-microglobulin–/– nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice resulted in significantly higher levels of engraftment of both green fluorescent protein–positive (GFP+) and GFP– populations as compared with controls. GFP+ cells in bone marrow and spleen of animals that had received transplants gave rise to an immature CD4+CD8+ T-cell population, whereas B-cell development was blocked. These results indicate that activation of Notch4 results in enhanced stem cell activity, reduced differentiation, and altered lymphoid development, suggesting it may influence both stem cells and the fate of the common lymphoid progenitor.

scholarly journals Diversity of Nuclear Lamin A/C Action as a Key to Tissue-Specific Regulation of Cellular Identity in Health and Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Anna Malashicheva ◽  
Kseniya Perepelina
Keyword(s):  
Cell Differentiation ◽  
Identity Development ◽  
Cell Fate ◽  
Critical Role ◽  
Nuclear Lamina ◽  
Lamin A ◽  
Cell Fate Decisions ◽  
Genes Encoding ◽  
Specific Regulation ◽  
Differentiation Status

A-type lamins are the main structural components of the nucleus, which are mainly localized at the nucleus periphery. First of all, A-type lamins, together with B-type lamins and proteins of the inner nuclear membrane, form a stiff structure—the nuclear lamina. Besides maintaining the nucleus cell shape, A-type lamins play a critical role in many cellular events, such as gene transcription and epigenetic regulation. Nowadays it is clear that lamins play a very important role in determining cell fate decisions. Various mutations in genes encoding A-type lamins lead to damages of different types of tissues in humans, collectively known as laminopathies, and it is clear that A-type lamins are involved in the regulation of cell differentiation and stemness. However, the mechanisms of this regulation remain unclear. In this review, we discuss how A-type lamins can execute their regulatory role in determining the differentiation status of a cell. We have summarized recent data focused on lamin A/C action mechanisms in regulation of cell differentiation and identity development of stem cells of different origin. We also discuss how this knowledge can promote further research toward a deeper understanding of the role of lamin A/C mutations in laminopathies.

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