Bazooka/Par3 cooperates with Sanpodo for the assembly of Notch clusters following asymmetric division of Drosophila sensory organ precursor cells

In multiple cell lineages, Delta-Notch signalling regulates cell fate decisions owing to unidirectional signalling between daughter cells. In Drosophila pupal sensory organ lineage, Notch regulates the intra-lineage pIIa/pIIb fate decision at cytokinesis. Notch and Delta that localise apically and basally at the pIIa-pIIb interface are expressed at low levels and their residence time at the plasma membrane is in the order of minutes. How Delta can effectively interact with Notch to trigger signalling from a large plasma membrane area remains poorly understood. Here, we report that the signalling interface possesses a unique apicobasal polarity with Par3/Bazooka localising in the form of nano-clusters at the apical and basal level. Notch is preferentially targeted to the pIIa-pIIb interface, where it co-clusters with Bazooka and its cofactor Sanpodo. Clusters whose assembly relies on Bazooka and Sanpodo activities are also positive for Neuralized, the E3 ligase required for Delta-activity. We propose that the nano-clusters act as snap buttons at the new pIIa-pIIb interface to allow efficient intra-lineage signalling.

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Bazooka/Par3 cooperates with Sanpodo for the assembly of Notch signaling clusters following asymmetric division of Drosophila sensory organ precursor cells

10.1101/2021.01.19.427226 ◽

2021 ◽

Author(s):

Elise Houssin ◽

Mathieu Pinot ◽

Karen Bellec ◽

Roland Le Borgne

Keyword(s):

Plasma Membrane ◽

Notch Signaling ◽

Cell Fate ◽

Sensory Organ ◽

Cell Fate Decisions ◽

Daughter Cells ◽

Delta Activity ◽

Multiple Cell ◽

Sensory Organ Precursor ◽

Fate Decision

SummaryIn multiple cell lineages, Delta-Notch signaling regulates cell fate decisions owing to unidirectional signaling between daughter cells. In Drosophila pupal sensory organ lineage, Notch regulates pIIa/pIIb fate decision at cytokinesis. Notch and Delta that localize apically and basally at the pIIa-pIIb interface, are expressed at low levels and their residence time at the plasma membrane is in the order of the minute. How Delta can effectively interact with Notch to trigger signaling from a large plasma membrane remains poorly understood. Here, we report that the signaling interface possesses a unique apicobasal polarity with Par3/Bazooka localizing in the form of nano-clusters at the apical and basal level. Notch is preferentially targeted to the pIIa-pIIb interface where it co-clusters with Bazooka and the Notch cofactor Sanpodo. Clusters whose assembly relies on Bazooka and Sanpodo activities, are also positive for Neuralized, the E3 ligase required for Delta-activity. We propose that the nano-clusters act as snap buttons at the new pIIa-pIIb interface to allow efficient intra-lineage signaling.

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Antagonistic activities of Suppressor of Hairless and Hairless control alternative cell fates in the Drosophila adult epidermis

Development ◽

10.1242/dev.120.6.1433 ◽

1994 ◽

Vol 120 (6) ◽

pp. 1433-1441 ◽

Cited By ~ 28

Author(s):

F. Schweisguth ◽

J.W. Posakony

Keyword(s):

Cell Fate ◽

Imaginal Disc ◽

Sensory Organ ◽

Cell Fate Decisions ◽

Suppressor Of Hairless ◽

Disc Cells ◽

Sensory Organ Precursor ◽

Fate Decision ◽

Mutant Phenotypes ◽

Proneural Cluster

Successive alternative cell fate choices in the imaginal disc epithelium lead to the differentiation of a relatively invariant pattern of multicellular adult sensory organs in Drosophila. We show here that the activity of Suppressor of Hairless is required for both the sensory organ precursor (SOP) versus epidermal cell fate decision, and for the trichogen (shaft) versus tormogen (socket) cell fate choice. Complete loss of Suppressor of Hairless function causes most proneural cluster cells to accumulate high levels of the achaete and Delta proteins and to adopt the SOP fate. Late or partial reduction in Suppressor of Hairless activity leads to the apparent transformation of the tormogen (socket) cell into a second trichogen (shaft) cell, producing a ‘double shaft’ phenotype. We find that overexpression of Suppressor of Hairless has the opposite phenotypic effects. SOP determination is prevented by an early excess of Suppressor of Hairless activity, while at a later stage, the trichogen (shaft) cell is transformed into a second tormogen (socket) cell, resulting in ‘double socket’ bristles. We conclude that, for two different cell fate decisions in adult sensory organ development, decreasing or increasing the level of Suppressor of Hairless function confers mutant phenotypes that closely resemble those associated with gain and loss of Hairless activity, respectively. These results, along with the intermediate SOP phenotype observed in Suppressor of Hairless; Hairless double mutant imaginal discs, suggest that the two genes act antagonistically to commit imaginal disc cells stably to alternative fates.

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

Development ◽

10.1242/dev.121.11.3745 ◽

1995 ◽

Vol 121 (11) ◽

pp. 3745-3752 ◽

Cited By ~ 13

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.

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Activation of the MAPK Module from Different Spatial Locations Generates Distinct System Outputs

Molecular Biology of the Cell ◽

10.1091/mbc.e08-04-0407 ◽

2008 ◽

Vol 19 (11) ◽

pp. 4776-4784 ◽

Cited By ~ 56

Author(s):

Kerry Inder ◽

Angus Harding ◽

Sarah J. Plowman ◽

Mark R. Philips ◽

Robert G. Parton ◽

...

Keyword(s):

Plasma Membrane ◽

Cell Fate ◽

Mapk Pathway ◽

Cell Fate Decisions ◽

Raf Kinase ◽

System Output ◽

Multiple Cell ◽

Spatial Locations ◽

Distinct Membrane ◽

Striking Contrast

The Ras/Raf/MEK/ERK (MAPK) pathway directs multiple cell fate decisions within a single cell. How different system outputs are generated is unknown. Here we explore whether activating the MAPK module from different membrane environments can rewire system output. We identify two classes of nanoscale environment within the plasma membrane. The first, which corresponds to nanoclusters occupied by GTP-loaded H-, N- or K-Ras, supports Raf activation and amplifies low Raf kinase input to generate a digital ERKpp output. The second class, which corresponds to nanoclusters occupied by GDP-loaded Ras, cannot activate Raf and therefore does not activate the MAPK module, illustrating how lateral segregation on plasma membrane influences signal output. The MAPK module is activated at the Golgi, but in striking contrast to the plasma membrane, ERKpp output is analog. Different modes of Raf activation precisely correlate with these different ERKpp system outputs. Intriguingly, the Golgi contains two distinct membrane environments that generate ERKpp, but only one is competent to drive PC12 cell differentiation. The MAPK module is not activated from the ER. Taken together these data clearly demonstrate that the different nanoscale environments available to Ras generate distinct circuit configurations for the MAPK module, bestowing cells with a simple mechanism to generate multiple system outputs from a single cascade.

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A dual function ofphyllopodinDrosophilaexternal sensory organ development: cell fate specification of sensory organ precursor and its progeny

Development ◽

10.1242/dev.128.14.2699 ◽

2001 ◽

Vol 128 (14) ◽

pp. 2699-2710 ◽

Cited By ~ 2

Author(s):

Haiwei Pi ◽

Hui-Ju Wu ◽

Cheng-Ting Chien

Keyword(s):

Cell Fate ◽

Mrna Level ◽

Sensory Organ ◽

Dual Function ◽

Organ Development ◽

Cell Fate Specification ◽

Genetic Switch ◽

Fate Specification ◽

Daughter Cells ◽

Sensory Organ Precursor

During Drosophila external sensory organ development, one sensory organ precursor (SOP) arises from a proneural cluster, and undergoes asymmetrical cell divisions to produce an external sensory (es) organ made up of different types of daughter cells. We show that phyllopod (phyl), previously identified to be essential for R7 photoreceptor differentiation, is required in two stages of es organ development: the formation of SOP cells and cell fate specification of SOP progeny. Loss-of-function mutations in phyl result in failure of SOP formation, which leads to missing bristles in adult flies. At a later stage of es organ development, phyl mutations cause the first cell division of the SOP lineage to generate two identical daughters, leading to the fate transformation of neurons and sheath cells to hair cells and socket cells. Conversely, misexpression of phyl promotes ectopic SOP formation, and causes opposite fate transformation in SOP daughter cells. Thus, phyl functions as a genetic switch in specifying the fate of the SOP cells and their progeny. We further show that seven in absentia (sina), another gene required for R7 cell fate differentiation, is also involved in es organ development. Genetic interactions among phyl, sina and tramtrack (ttk) suggest that phyl and sina function in bristle development by antagonizing ttk activity, and ttk acts downstream of phyl. It has been shown previously that Notch (N) mutations induce formation of supernumerary SOP cells, and transformation from hair and socket cells to neurons. We further demonstrate that phyl acts epistatically to N. phyl is expressed specifically in SOP cells and other neural precursors, and its mRNA level is negatively regulated by N signaling. Thus, these analyses demonstrate that phyl acts downstream of N signaling in controlling cell fates in es organ development.

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

Genetics ◽

10.1093/genetics/141.4.1491 ◽

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.

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SEL-5, A Serine/Threonine Kinase That Facilitates lin-12 Activity in Caenorhabditis elegans

Genetics ◽

10.1093/genetics/153.4.1641 ◽

1999 ◽

Vol 153 (4) ◽

pp. 1641-1654 ◽

Cited By ~ 1

Author(s):

Hanna Fares ◽

Iva Greenwald

Keyword(s):

Cell Fate ◽

Point Mutations ◽

Kinase Domain ◽

Terminal Region ◽

Serine Threonine Kinase ◽

Intracellular Domain ◽

Cell Fate Decisions ◽

Threonine Kinase ◽

Amino Terminal ◽

Fate Decision

Abstract Ligands present on neighboring cells activate receptors of the LIN-12/Notch family by inducing a proteolytic cleavage event that releases the intracellular domain. Mutations that appear to eliminate sel-5 activity are able to suppress constitutive activity of lin-12(d) mutations that are point mutations in the extracellular domain of LIN-12, but cannot suppress lin-12(intra), the untethered intracellular domain. These results suggest that sel-5 acts prior to or during ligand-dependent release of the intracellular domain. In addition, sel-5 suppression of lin-12(d) mutations is tissue specific: loss of sel-5 activity can suppress defects in the anchor cell/ventral uterine precursor cell fate decision and a sex myoblast/coelomocyte decision, but cannot suppress defects in two different ventral hypodermal cell fate decisions in hermaphrodites and males. sel-5 encodes at least two proteins, from alternatively spliced mRNAs, that share an amino-terminal region and differ in the carboxy-terminal region. The amino-terminal region contains the hallmarks of a serine/threonine kinase domain, which is most similar to mammalian GAK1 and yeast Pak1p.

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Cell fate clusters in ICM organoids arise from cell fate heredity and division: a modelling approach

Scientific Reports ◽

10.1038/s41598-020-80141-3 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Tim Liebisch ◽

Armin Drusko ◽

Biena Mathew ◽

Ernst H. K. Stelzer ◽

Sabine C. Fischer ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Division ◽

Cell Fate ◽

Inner Cell Mass ◽

Cell Mass ◽

Cell Lineage ◽

Cell Fate Decision ◽

Cell Fate Decisions ◽

Chemical Signalling ◽

Fate Decision

AbstractDuring the mammalian preimplantation phase, cells undergo two subsequent cell fate decisions. During the first decision, the trophectoderm and the inner cell mass are formed. Subsequently, the inner cell mass segregates into the epiblast and the primitive endoderm. Inner cell mass organoids represent an experimental model system, mimicking the second cell fate decision. It has been shown that cells of the same fate tend to cluster stronger than expected for random cell fate decisions. Three major processes are hypothesised to contribute to the cell fate arrangements: (1) chemical signalling; (2) cell sorting; and (3) cell proliferation. In order to quantify the influence of cell proliferation on the observed cell lineage type clustering, we developed an agent-based model accounting for mechanical cell–cell interaction, i.e. adhesion and repulsion, cell division, stochastic cell fate decision and cell fate heredity. The model supports the hypothesis that initial cell fate acquisition is a stochastically driven process, taking place in the early development of inner cell mass organoids. Further, we show that the observed neighbourhood structures can emerge solely due to cell fate heredity during cell division.

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Conservation of the Notch signalling pathway in mammalian neurogenesis

Development ◽

10.1242/dev.124.6.1139 ◽

1997 ◽

Vol 124 (6) ◽

pp. 1139-1148 ◽

Cited By ~ 31

Author(s):

J.L. Pompa de la ◽

A. Wakeham ◽

K.M. Correia ◽

E. Samper ◽

S. Brown ◽

...

Keyword(s):

Cell Fate ◽

Notch Pathway ◽

Stem Cell Differentiation ◽

Notch Signalling ◽

Signalling Pathway ◽

Notch Signalling Pathway ◽

Altered Expression ◽

Cell Fate Decisions ◽

Targeted Mutation ◽

Multiple Cell

The Notch pathway functions in multiple cell fate determination processes in invertebrate embryos, including the decision between the neuroblast and epidermoblast lineages in Drosophila. In the mouse, targeted mutation of the Notch pathway genes Notch1 and RBP-Jk has demonstrated a role for these genes in somite segmentation, but a function in neurogenesis and in cell fate decisions has not been shown. Here we show that these mutations lead to altered expression of the Notch signalling pathway homologues Hes-5, Mash-1 and Dll1, resulting in enhanced neurogenesis. Precocious neuronal differentiation is indicated by the expanded expression domains of Math4A, neuroD and NSCL-1. The RBP-Jk mutation has stronger effects on expression of these genes than does the Notch1 mutation, consistent with functional redundancy of Notch genes in neurogenesis. Our results demonstrate conservation of the Notch pathway and its regulatory mechanisms from fly to mouse, and support a role for the murine Notch signalling pathway in the regulation of neural stem cell differentiation.

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Density of the Notch ligand Delta1 determines generation of B and T cell precursors from hematopoietic stem cells

Journal of Experimental Medicine ◽

10.1084/jem.20042450 ◽

2005 ◽

Vol 201 (9) ◽

pp. 1361-1366 ◽

Cited By ~ 92

Author(s):

Mari H. Dallas ◽

Barbara Varnum-Finney ◽

Colleen Delaney ◽

Keizo Kato ◽

Irwin D. Bernstein

Keyword(s):

T Cell ◽

B Cell ◽

Cell Fate ◽

Precursor Cells ◽

Hematopoietic Stem ◽

Notch Ligand ◽

Murine Bone Marrow ◽

Cell Fate Decisions ◽

Multiple Cell ◽

B Cell Precursors

Notch signaling regulates multiple cell fate decisions by hematopoietic precursors. To address whether different amounts of Notch ligand influence lineage choices, we cultured murine bone marrow lin−Sca-1+c-kit+ cells with increasing densities of immobilized Delta1ext-IgG consisting of the extracellular domain of Delta1 fused to the Fc domain of human IgG1. We found that relatively lower densities of Delta1ext-IgG enhanced the generation of Sca-1+c-kit+ cells, Thy1+CD25+ early T cell precursors, and B220+CD43−/lo cells that, when cocultured with OP9 stroma cells, differentiated into CD19+ early B cell precursors. Higher densities of Delta1ext-IgG also enhanced the generation of Sca-1+c-kit+ precursor cells and promoted the development of Thy1+CD25+ cells, but inhibited the development of B220+CD43−/lo cells. Analyses of further isolated precursor populations suggested that the enhanced generation of T and B cell precursors resulted from the effects on multipotent rather than lymphoid-committed precursors. The results demonstrate the density-dependent effects of Delta1 on fate decisions of hematopoietic precursors at multiple maturational stages and substantiate the previously unrecognized ability of Delta1 to enhance the development of both early B and T precursor cells.

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