Recently, an important role of Notch activation for Ras-induced transformation of glial cells and for glioma growth and survival has been demonstrated. It was concluded that activation of Notch-signaling may represent a new target for glioblastoma multiforme (GBM) therapy. We now analyzed five GBM cell lines (Tx3095, Tx3868, U87, U118, ...

Hedgehog (HH) signaling is important in the pathogenesis of several malignancies. Recently, we described that HH signaling proteins are commonly expressed in diffuse large B-cell lymphoma (DLBCL); however, the functional role of HH pathway in DLBCL has not been explored. Here, we assessed the possibility that HH pathway activation contributes ...

The Notch signaling pathway regulates specification of zebrafish liver progenitor cells towards a biliary cell fate. Here, using staged administration of a pharmacological inhibitor of Notch receptor processing, we show that activation of the Notch pathway is also important for growth and expansion of the intrahepatic biliary network in zebrafish ...

We study the arrangements of recurved bristles on the anterior wing margin of wild-type and mutant Drosophila. The epidermal or neural fate of a proneural cell depends on the concentrations of proteins of the achaete-scute complex. At puparium formation, concentrations of proteins are nearly identical in all cells of the ...

It has become apparent that T cells require growth signals to maintain function and viability necessary to maintain proper immune homeostasis. One means by which cell extrinsic signals may mediate these effects is by sustaining sufficient basal cell metabolism to prevent cell atrophy. The role of metabolism and the specific ...

Correct tissue patterning during development involves multiple morphogenetic events that include specification of different cell fates, cell proliferation, cell death, and coordinated changes in cell shape, position, and adhesion. Here, we use the Drosophila retina to explore the molecular mechanisms that regulate and integrate these various events. In a previous ...

Primitive endoderm (PE) and epiblast (EPI) are two lineages derived from the inner cell mass (ICM) of the E3.5 blastocyst. Recent studies showed that EPI and PE progenitors expressing the lineage-specific transcriptional factors Nanog and Gata6, respectively, arise progressively as the ICM develops. Subsequent sorting of the two progenitors during ...

During dorsal closure in Drosophila, signaling events in the dorsalmost row of epidermal cells (DME cells) direct the migration of lateral epidermal sheets towards the dorsal midline where they fuse to enclose the embryo. A Jun amino-terminal kinase (JNK) cascade in the DME cells induces the expression of Decapentaplegic (Dpp). ...

In vertebrate embryos, the dorsal aorta and the posterior cardinal vein form in the trunk to comprise the original circulatory loop. Previous studies implicate Hedgehog (Hh) signaling in the development of the dorsal aorta. However, the mechanism controlling specification of artery versus vein remains unclear. Here, we investigated the cell-autonomous ...

Early events of B cell activation after B cell receptor (BCR) triggering have been well characterized. However, little is known about the steady state of the BCR on the cell surface. Here, we simultaneously visualize single BCR particles and components of the membrane skeleton. We show that an ezrin- and ...

Notch signaling has previously been implicated in the regulation of the cell fate of intestinal epithelial cells. However, the expression and function of Notch ligands in the human intestine remain largely unknown. In the present study, we showed that Notch ligands Delta-like 1 (Dll1) and Delta-like 4 (Dll4) are expressed ...

The Notch signaling pathway has been implicated in the development of several leukemia and lymphoma. In order to investigate the relationship between Notch signaling and acute myeloid leukemia (AML), in this study, we expressed a recombinant Notch ligand protein, the DSL domain of the human Jagged1 fused with GST (GST-Jag1). ...

The neurofibromatosis type 2 (NF2) tumor suppressor gene encodes merlin, a membrane/cytoskeleton protein necessary for the maintenance of contact inhibition of growth in cells. Bi-allelic inactivation of NF2 is known to cause multiple cancers in both humans and mice. However, the mechanism through which merlin exerts its tumor-suppressive function remains ...

We investigated cell shape changes during wound closure in the Drosophila larval epidermis. During reepithelialization, epidermal cells permanently change shape from pentagonal or hexagonal to irregular forms. This process requires zipper, a gene encoding the Drosophila nonmuscle myosin II heavy chain. Following wounding, myosin II is localized at the wound ...

Understanding how stem and progenitor cells choose between alternative cell fates is a major challenge in developmental biology. Efforts to tackle this problem have been hampered by the scarcity of markers that can be used to predict cell division outcomes. Here we present a computational method, based on algorithmic information ...

This minireview examines the role of hypoxia, and hypoxia inducible factors (HIF-1 and HIF-2), in regulating the metabolism, function, and fate of cells of the nucleus pulposus in the intervertebral disk. We focus on the mechanisms by which both these hypoxia-sensitive transcription factors influence energy metabolism, radical dismutation, and expression ...

Photoreceptors, rods and cones are the most abundant cell type in the mammalian retina. However, the molecules that control their development are not fully understood. In studies of photoreceptor fate determination, we found that Blimp1 (Prdm1) is expressed transiently in developing photoreceptors. We analyzed the function of Blimp1 in the ...

Foxg1 is required for development of the ventral telencephalon in the embryonic mammalian forebrain. Although one existing hypothesis suggests that failed ventral telencephalic development in the absence of Foxg1 is due to reduced production of the morphogens sonic hedgehog (Shh) and fibroblast growth factor 8 (Fgf8), the possibility that telencephalic ...

Cancer cells are unequal in a tumor mass and in established cultures. This is attributable to cancer stem cells with the unique ability to self-renew and to generate differentiating progeny. This ability is controlled at the level of asymmetric division by mechanisms that are yet not well defined. We found ...

Cell-cell cooperativity in populations of motile and transiently interacting immune cells has been difficult to assess in the absence of tools to control proximity and communication. Here, we describe the generation of cell-laden microwells that can precisely control contact-mediated interactions and multicellular 'quorum' decisions in lymphocytes. Different types of fate ...

Primordial germ cells (PGCs) in Xenopus embryo are specified in the endodermal cell mass and migrate dorsally toward the future gonads. The role of the signal mediated by Notch and Suppressor of Hairless [Su(H)] was analyzed on the migrating PGCs at the tailbud stage. X-Notch-1 and X-Delta-1 are expressed in ...

Cell growth is regulated by two antagonistic processes: TOR signaling and autophagy. These processes integrate signals including growth factors, amino acids, and energy status to ensure that cell growth is appropriate to environmental conditions. Autophagy responds indirectly to the cellular milieu as a downstream inhibitory target of TOR signaling and ...

Lung development is the result of complex interactions between four tissues: epithelium, mesenchyme, mesothelium and endothelium. We marked the lineages experiencing Notch1 activation in these four cellular compartments during lung development and complemented this analysis by comparing the cell fate choices made in the absence of RBPjkappa, the essential DNA ...

Control of organ size by cell proliferation and survival is a fundamental developmental process, and its deregulation leads to cancer. However, the molecular mechanism underlying organ size control remains elusive in vertebrates. In Drosophila, the Hippo (Hpo) signaling pathway controls organ size by both restricting cell growth and proliferation and ...

Much laboratory-based information exists on quorum sensing, a type of bacterial cell-to-cell communication that depends upon exchanges of molecular signals between neighboring cells. However, little is known about how this and other microbial sensing systems operate in nature. Geochemical and biological modifications of signals probably occur in extracellular environments, and ...

Interleukin-1 (IL-1)-mediated signaling in T cells is essential for T helper 17 (Th17) cell differentiation. We showed here that SIGIRR, a negative regulator of IL-1 receptor and Toll-like receptor signaling, was induced during Th17 cell lineage commitment and governed Th17 cell differentiation and expansion through its inhibitory effects on IL-1 ...

It has long been appreciated that spatiotemporal dynamics of cell migration are under the control of intracellular signaling pathways, which are mediated by adhesion receptors and other transducers of extracellular cues. Further, there is ample evidence that aspects of cell migration are stochastic: how else could it exhibit directional persistence ...

In Drosophila, mitotic neural progenitor cells asymmetrically segregate the cell fate determinant Numb in order to block Notch signaling in only one of the two daughter cells. Sanpodo, a membrane protein required for Notch signaling in asymmetrically dividing cells, is sequestered from the plasma membrane to intracellular vesicles in a ...

Crx is a transcription factor which is predominantly expressed in developing and mature photoreceptor cells in the retina, and plays a crucial role in the terminal differentiation of both rods and cones. Crx is one of the earliest-expressed genes specifically in photoreceptor precursors, allowing us to trace photoreceptor precursor cells ...

Evidence emerging from a variety of approaches used in different species suggests that Müller cell function may extend beyond its role of maintaining retinal homeostasis to that of progenitors in the adult retina. Enriched Müller cells in vitro or those that re-enter cell cycle in response to neurotoxin-damage to retina ...

Despite the well-documented association between loss of E-cadherin and carcinogenesis, as well as the link between restoration of its expression and suppression of proliferation in carcinoma cells, the ability of E-cadherin to modulate growth-promoting cell signalling in normal epithelial cells is less well understood and frequently contradictory. The potential for ...

Segments are fundamental units in animal development which are made of distinct cell lineages separated by boundaries. Although boundaries show limited plasticity during their formation for sharpening, cell lineages make compartments that become tightly restricted as development goes on. Here, we characterize a unique case of breaking of the segment ...

BACKGROUND: C. elegans TGF-beta-like Sma/Mab signaling pathway regulates both body size and sensory ray patterning. Most of the components in this pathway were initially identified by genetic screens based on the small body phenotype, and many of these mutants display sensory ray patterning defect. At the cellular level, little is ...

Morphogen gradients play a fundamental role in organ patterning and organ growth. Unlike their role in patterning, their function in regulating the growth and the size of organs is poorly understood. How and why do morphogen gradients exert their mitogenic effects to generate uniform proliferation in developing organs, and by ...

Cell types are typically defined by expression of a unique combination of genes, rather than a single gene. Intersectional methods therefore become crucial to selectively access these cells for higher resolution fate mapping and functional manipulations. Here, we discuss one such intersectional method. Two recombinase systems (Cre/loxP and Flp/FRT) work ...

Differentiation of neural retinal precursor (NRP) cells in vertebrates follows an established order of cell-fate determination associated with exit from the cell cycle. Wnt signaling regulates cell cycle in colon carcinoma cells and has been implicated in different aspects of retinal development in various species. To better understand the biological ...

Drosophila development is a tightly regulated process involving metamorphosis of a relatively less mobile larva to a highly motile adult, triggered by secretion of 20-hydroxyecdysone. Under the influence of ecdysone, most of the larval tissues degenerate, while the imaginal cells differentiate and form adult specific structures. Although the larval Malpighian ...

Cajal-Retzius (CR) cells play a key role in the formation of the cerebral cortex. These pioneer neurons are distributed throughout the cortical marginal zone in distinct graded distributions. Fate mapping and cell lineage tracing studies have recently shown that CR cells arise from restricted domains of the pallial ventricular zone, ...

Cells are sequentially recruited during formation of the Drosophila compound eye. A few simple rules are reiteratively utilized to control successive steps of eye assembly. Two themes emerge: the interplay between cell signaling and competence determines diversity of cell types and selective cell adhesion determines spatial patterns of cells. Cell ...

During the initial stages of carcinogenesis, transformation events occur in a single cell within an epithelial monolayer. However, it remains unknown what happens at the interface between normal and transformed epithelial cells during this process. In Drosophila, it has been recently shown that normal and transformed cells compete with each ...

Embryonic stem (ES) cells hold considerable promise as a source of cells with therapeutic potential, including cells that can be used for drug screening and in cell replacement therapies. Differentiation of ES cells into the somatic lineages is a regulated process; before the promise of these cells can be realised ...

The different cell types in an animal are often considered to be specified by combinations of transcription factors, and defined by marker gene expression. This paradigm is challenged, however, in stem cell research and application. Using a mouse embryonic stem cell (mESC) culture system, here we show that the expression ...

Although cell fate specification is tightly controlled to yield highly reproducible results and avoid extreme variation, developmental programs often incorporate stochastic mechanisms to diversify cell types. Stochastic specification phenomena are observed in a wide range of species and an assorted set of developmental contexts. In bacteria, stochastic mechanisms are utilized ...

During development, the Drosophila wing primordium undergoes a dramatic increase in cell number and mass under the control of the long-range morphogens Wingless (Wg, a Wnt) and Decapentaplegic (Dpp, a BMP). This process depends in part on the capacity of wing cells to recruit neighboring, non-wing cells into the wing ...

During development, proliferating cells are organized into compartments with boundaries across which cells fail to intermix. Compartment boundaries are often attributed to differential cell-cell adhesion between separate compartments. However, tension generated by actomyosin cables at boundaries can also function as a barrier that prevents cell mixing.

Fate maps depict how cells relate together through past lineage relationships, and are useful tools for studying developmental and somatic processes. However, with existing technologies, it has not been possible to generate detailed fate maps of complex organisms such as the mouse. We and others have therefore proposed a novel ...

Math5-null mutation results in the loss of retinal ganglion cells (RGCs) and in a concurrent increase of amacrine and cone cells. However, it remains unclear whether there is a cell fate switch of Math5-lineage cells in the absence of Math5 and whether MATH5 cell-autonomously regulates the differentiation of the above ...

BACKGROUND: Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates a multitude of cellular functions, including cell proliferation, survival, migration and angiogenesis. S1P mediates its effects either by signaling through G protein-coupled receptors (GPCRs) or through an intracellular mode of action. In this study, we have investigated the mechanism behind S1P-induced ...

Members of IL-6 family cytokines, such as leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF), activate the common signal-transducing receptor gp130. We and others have previously shown that application of exogenous gp130 ligands promotes photoreceptor survival in light-induced and inherited retinal degeneration in animal models. While there is strong ...

BACKGROUND: In the face of changing environmental conditions, the mechanisms underlying stress responses in diverse organisms are of increasing interest. In vertebrates, Drosophila, and Caenorhabditis elegans, FoxO transcription factors mediate cellular responses to stress, including oxidative stress and dietary restriction. Although FoxO genes have been identified in early-arising animal lineages ...