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  • 1
    Keywords: CELLS ; CELL ; INHIBITION ; GENE-EXPRESSION ; TISSUE ; ACTIVATION ; MECHANISM ; SUFFICIENT ; BIOLOGY ; antibodies ; antibody ; MOUSE ; REGION ; REGIONS ; XENOPUS ; MIGRATION ; epidermis ; ANTAGONIST ; SPEMANN ORGANIZER ; WNT ; signaling ; interaction ; NEURAL INDUCTION ; ANTERIOR-POSTERIOR AXIS ; analysis ; USA ; neural crest ; INHIBIT ; MOUSE EMBRYOS ; WNT/BETA-CATENIN ; ZEBRAFISH ; BMP GRADIENT ; dkkl ; EMBRYONIC HEAD INDUCTION ; QUAIL-CHICK CHIMERAS ; snail1 ; snail2 ; XENOPUS-EMBRYOS
    Abstract: It is known the interactions between the neural plate and epidermis generate neural crest (NC), but it is unknown why the NC develops only at the lateral border of the neural plate and not in the anterior fold. Using grafting experiments we show that there is a previously unidentified mechanism that precludes NC from the anterior region. We identify prechordal mesoderm as the tissue that inhibits NC in the anterior territory and show that the Wnt/beta-catenin antagonist Dkk1, secreted by this tissue, is sufficient to mimic this NC inhibition. We show that Dkk1 is required for preventing the formation of NC in the anterior neural folds as loss-of-function experiments using a Dkk1 blocking antibody in Xenopus as well as the analysis of Dkk1-null mouse embryos transform the anterior neural fold into NC. This can be mimicked by Wnt/beta-catenin signaling activation without affecting the anterior posterior patterning of the neural plate, or placodal specification. Finally, we show that the NC cells induced at the anterior neural fold are able to migrate and differentiate as normal NC. These results demonstrate that anterior regions of the embryo lack NC because of a mechanism, conserved from fish to mammals, that suppresses Wnt/beta-catenin signaling via Dkk1. (C) 2007 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17669393
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  • 2
    Keywords: GENE ; PROTEIN ; ENCODES ; MELANOGASTER ; BETA ; MORPHOGENESIS ; NUCLEOCYTOPLASMIC TRANSPORT ; Kelch ; SMALL GTPASE RAN ; NUCLEAR-PORE
    Abstract: The interstitial deletion D14 affecting the importin-alpha 2 gene of Drosophila, or imp-alpha 2(D14), causes recessive female sterility characterized by a block of nurse cell-oocyte transport during oogenesis. In wild-type egg chambers, the Imp-alpha 2 protein is uniformly distributed in the nurse cell cytoplasm with a moderate accumulation along the oocyte cortex. Cytochalasin D treatment of wild-type egg chambers disrupts the in vivo association of Imp-alpha 2 with F-actin and results in its release from the oocyte cortex and its transfer into nurse cell nuclei. Binding assay shows that the interaction of Imp-alpha 2 with F-actin, albeit not monomeric actin, requires the occurrence of NLS peptides. Phenotypic analysis of imp-alpha 2(D14) ovaries reveals that the block of nurse cell-oocyte transport results from the occlusion of the ring canals that constitute cytoplasmic bridges between the nurse cells and the oocyte. Immunohistochemistry shows that, although the Imp-alpha2 protein cannot be detected on the ring canals, the Kelch protein, a known ring canal component, fails to bind to ring canals in imp-alpha 2(D14) egg chambers. Since loss-of-function mutations of kelch results in a similar dumpless phenotype, we propose that the Imp-alpha 2 protein plays a critical role in Kelch function by regulating its deposition on ring canals during their assembly.
    Type of Publication: Journal article published
    PubMed ID: 12435357
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  • 3
    Keywords: beta-catenin ; HOST-DEFENSE ; HOMEOSTASIS ; INNATE IMMUNE-RESPONSES ; BACTERIAL-INFECTION ; STEM-CELL PROLIFERATION ; MULTIPLE PATHWAYS ; DROSOPHILA MIDGUT ; ADULT MIDGUT REGENERATION ; DPP
    Abstract: Maintaining tissue homeostasis is a critical process during infection and inflammation. Tissues with a high intrinsic turnover, such as the intestinal epithelium, must launch a rapid response to infections while simultaneously coordinating cell proliferation and differentiation decisions. In this study, we searched for genes required for regeneration of the Drosophila intestine, and thereby affecting overall organism survival after infection with pathogenic bacteria. We found that Dpp/Gbb (BMP) signaling is essential for normal midgut regeneration, and that infection induces the BMP signaling ligands Dpp and Gbb. We demonstrate that Dpp is induced in visceral muscle and required for signaling activation. Subsequently, Gbb is induced in enterocytes after oral infection. Loss-of Dpp signaling in ISCs and transient committed progenitors called enteroblasts (EBs), or in EBs alone, led to a blockage in EC differentiation or maturation. Furthermore, our data show that down-regulation of Dpp signaling in the precursor cells including EBs also resulted in an increased number of abnormally small Pdm1-positive cells, suggesting a role of Dpp/Gbb signaling in EC growth. In addition, we show that Dpp/Gbb signaling acted downstream or in parallel to the Notch pathway to promote EC differentiation and growth. Our results suggest that Dpp/BMP signaling plays an important role in EBs to maintain tissue integrity and homeostasis during pathogenic infections.
    Type of Publication: Journal article published
    PubMed ID: 25553980
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  • 4
    Keywords: CANCER ; GROWTH ; CELL ; KINASE ; PATHWAY ; METABOLISM ; ACTIVATION ; COMPLEX ; COMPLEXES ; BIOLOGY ; PHOSPHORYLATION ; culture ; ACID ; Drosophila ; SIGNALING PATHWAY ; PHENOTYPE ; AMINO-ACIDS ; GTPASE ; insulin ; CELL-GROWTH ; signaling ; SCIENCE ; LIFE ; BODY-SIZE ; MUTANTS ; SIZE ; RHO ; mTOR ; amino acids ; HVPS34 ; Rag GTPase ; RAG GTPASES ; TOR
    Abstract: The TOR pathway mediates nutrient-responsive regulation of cell growth and metabolism in animals TOR Complex 1 activity depends, amongst other things, on amino acid availability MAP4K3 was recently implicated in amino-acid signaling in cell culture We report here the physiological characterization of MAP4K3 mutant flies Flies lacking MAP4K3 have reduced TORC1 activity detected by phosphorylation of S6K and 4EBP Furthermore MAP4K3 mutants display phenotypes characteristic of low TORC1 activity and low nutrient availability, such as reduced growth rate, small body size, and low lipid reserves The differences between control and MAP4K3 mutant animals diminish when animals are reared in low-nutrient conditions. suggesting that the ability of TOR to sense amino acids is most important when nutrients are abundant Lastly, we show physical interaction between MAP4K3 and the Rag GTPases raising the possibility they might be acting in one signaling pathway (C) 2010 Elsevier Inc All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 20457147
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  • 5
    Abstract: Mechanisms that govern cell-fate specification within developing epithelia have been intensely investigated, with many of the critical intercellular signaling pathways identified, and well characterized. Much less is known, however, about downstream events that drive the morphological differentiation of these cells, once their fate has been determined. In the Drosophila wing-blade epithelium, two cell types predominate: vein and intervein. After cell proliferation is complete and adhesive cell-cell contacts have been refined, the vast majority of intervein cells adopt a hexagonal morphology. Within vein territories, however, cell-shape refinement results in trapezoids. Signaling events that differentiate between vein and intervein cell fates are well understood, but the genetic pathways underlying vein/intervein cyto-architectural differences remain largely undescribed. We show here that the Rap1 GTPase plays a critical role in determining cell-type-specific morphologies within the developing wing epithelium. Rap1, together with its effector Canoe, promotes symmetric distribution of the adhesion molecule DE-cadherin about the apicolateral circumference of epithelial cells. We provide evidence that in presumptive vein tissue Rap1/Canoe activity is down-regulated, resulting in adhesive asymmetries and non-hexagonal cell morphologies. In particular Canoe levels are reduced in vein cells as they morphologically differentiate. We also demonstrate that over-expression of Rap1 disrupts vein formation both in the developing epithelium and the adult wing blade. Therefore, vein/intervein morphological differences result, at least in part, from the patterned regulation of Rap1 activity.
    Type of Publication: Journal article published
    PubMed ID: 22776378
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  • 6
    Keywords: INTRAFLAGELLAR TRANSPORT ; dopaminergic neurons ; MIDBRAIN ; PRIMARY CILIA ; SHH ; Ift88
    Abstract: Midbrain dopaminergic (mDA) neurons modulate various motor and cognitive functions, and their dysfunction or degeneration has been implicated in several psychiatric diseases. Both Sonic Hedgehog (Shh) and Wnt signaling pathways have been shown to be essential for normal development of mDA neurons. Primary cilia are critical for the development of a number of structures in the brain by serving as a hub for essential developmental signaling cascades, but their role in the generation of mDA neurons has not been examined. We analyzed mutant mouse lines deficient in the intraflagellar transport protein IFT88, which is critical for primary cilia function. Conditional inactivation of Ift88 in the midbrain after E9.0 results in progressive loss of primary cilia, a decreased size of the mDA progenitor domain, and a reduction in mDA neurons. We identified Shh signaling as the primary cause of these defects, since conditional inactivation of the Shh signaling pathway after E9.0, through genetic ablation of Gli2 and Gli3 in the midbrain, results in a phenotype basically identical to the one seen in Ift88 conditional mutants. Moreover, the expansion of the mDA progenitor domain observed when Shh signaling is constitutively activated does not occur in absence of Ift88. In contrast, clusters of Shh-responding progenitors are maintained in the ventral midbrain of the hypomorphic Ift88 mouse mutant, cobblestone. Despite the residual Shh signaling, the integrity of the mDA progenitor domain is severely disturbed, and consequently very few mDA neurons are generated in cobblestone mutants. Our results identify for the first time a crucial role of primary cilia in the induction of mDA progenitors, define a narrow time window in which Shh-mediated signaling is dependent upon normal primary cilia function for this purpose, and suggest that later Wnt signaling-dependent events act independently of primary cilia.
    Type of Publication: Journal article published
    PubMed ID: 26542012
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  • 7
    Abstract: Spermiogenesis is the final phase during sperm cell development in which round spermatids undergo dramatic morphological changes to generate spermatozoa. Here we report that the serine/threonine kinase Stk33 is essential for the differentiation of round spermatids into functional sperm cells and male fertility. Constitutive Stk33 deletion in mice results in severely malformed and immotile spermatozoa that are particularly characterized by disordered structural tail elements. Stk33 expression first appears in primary spermatocytes, and targeted deletion of Stk33 in these cells recapitulates the defects observed in constitutive knockout mice, confirming a germ cell-intrinsic function. Stk33 protein resides in the cytoplasm and partially co-localizes with the caudal end of the manchette, a transient structure that guides tail elongation, in elongating spermatids, and loss of Stk33 leads to the appearance of a tight, straight and elongated manchette. Together, these results identify Stk33 as an essential regulator of spermatid differentiation and male fertility.
    Type of Publication: Journal article published
    PubMed ID: 29155043
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  • 8
    Keywords: CELLS ; EXPRESSION ; Germany ; SYSTEM ; GENE ; GENES ; GENOME ; HYBRIDIZATION ; microarray ; transcription ; DIFFERENTIATION ; validation ; TIME ; MACROPHAGES ; TRANSCRIPTION FACTOR ; INDUCTION ; NERVOUS-SYSTEM ; TRANSCRIPTION FACTORS ; IN-SITU ; ENCODES ; microarrays ; DESIGN ; Drosophila ; NUMBER ; genetics ; CENTRAL-NERVOUS-SYSTEM ; specificity ; expression profiling ; CELL-DIFFERENTIATION ; in situ hybridization ; SUBSET ; DEPENDENCE ; TARGET GENES ; function ; glial cells ; BARRIER FORMATION ; Drosophila embryogenesis ; EMBRYONIC NERVOUS-SYSTEM ; FATE ; gcm ; glial development ; glial genes ; IDENTIFIED NEUROBLASTS ; macrophage ; MOLECULAR MARKERS ; PROMOTING FACTOR ; SEPTATE JUNCTION
    Abstract: In the central nervous system of Drosophila, the induction of the glial cell fate is dependent on the transcription factor glial cells missing (gcm). Though a considerable number of other genes have been shown to be expressed in all or in subsets of glial cells, the course of glial cell differentiation and subtype specification is only poorly understood. This prompted us to design a whole genome microarray approach comparing gem gain-of-function and, for the first time, gem loss-of-function genetics to wildtype in time course experiments along embryogenesis. The microarray data were analyzed with special emphasis on the temporal profile of differential regulation. A comparison of both experiments enabled us to identify more than 300 potential gcm target genes. Validation by in situ hybridization revealed expression in glial cells, macrophages, and tendon cells (all three cell types depend on gem) for 70 genes, of which more than 50 had been unknown to be under gem control. Eighteen genes are exclusively expressed in glial cells, and their dependence on gem was confirmed in situ. Initial considerations regarding the role of the newly discovered glial genes are discussed based on gene ontology and the temporal profile and subtype specificity of their expression. This collection of glial genes provides an important basis for the clarification of the genetic network controlling various aspects of glial development and function. (c) 2006 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16762338
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  • 9
    Keywords: brain ; APOPTOSIS ; IN-VIVO ; FACTOR AP-2 ; MOUSE EMBRYOGENESIS ; neural crest ; sympathetic ; NEURAL CREST CELLS ; NEUROTRANSMITTER PHENOTYPE ; CHOLINERGIC DIFFERENTIATION ; PRECURSOR CELLS ; AP-2 alpha ; AP-2 beta ; CRANIOFACIAL DEVELOPMENT ; DRG ; NORADRENERGIC DIFFERENTIATION ; Parasympathetic ; Sensory ; TYROSINE-HYDROXYLASE
    Abstract: Differentiation of sympathetic neurons is controlled by a group of transcription factors, including Phox2b, Ascl1, Hand2 and Gata3, induced by bone morphogenetic proteins (BMPs) in progenitors located in ganglion primordia at the dorsal aorta. Here, we address the function of the transcription factors AP-2 beta and AP-2 alpha, expressed in migrating neural crest cells (NCC) and maintained in sympathetic progenitors and differentiated neurons. The elimination of both AP-2 alpha and AP-2 beta results in the virtually complete absence of sympathetic and sensory ganglia due to apoptotic cell death of migrating NCC. In the AP-2 beta knockout only sympathetic ganglia (SG) are targeted, leading to a reduction in ganglion size by about 40%, which is also caused by apoptotic death of neural crest progenitors. The conditional double knockout of AP-2 alpha and AP-2 beta in sympathetic progenitors and differentiated noradrenergic neurons results in a further decrease in neuron number, leading eventually to small sympathetic ganglion rudiments postnatally. The elimination of AP-2 beta also leads to the complete absence of noradrenergic neurons of the Locus coeruleus (LC). Whereas AP-2 alpha/beta transcription factors are in vivo not required for the onset or maintenance of noradrenergic differentiation, their essential survival functions are demonstrated for sympathetic progenitors and noradrenergic neurons.
    Type of Publication: Journal article published
    PubMed ID: 21539825
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  • 10
    Keywords: CYCLE PROGRESSION ; DROSOPHILA HOMOLOG ; PHOSPHOINOSITIDE 3-KINASE ; DEPENDENT PHOSPHORYLATION ; GROWTH-CONTROL ; TUMOR-SUPPRESSOR PATHWAY ; YES-ASSOCIATED PROTEIN ; ORGAN SIZE CONTROL ; HIPPO PATHWAY ; CARDIOMYOCYTE PROLIFERATION
    Abstract: The insulin/IGF signaling (IIS) pathway is a potent inducer of cell proliferation in normal development and in cancer. The mechanism by which this occurs, however, is not completely understood. The Hippo signaling pathway regulates cell proliferation via the transcriptional co-activator Yorkie/YAP, however the signaling inputs regulating Hippo activity are not fully elucidated. Here we present evidence linking these two conserved, oncogenic pathways in Drosophila and in mammalian cells. We find that activation of IIS and of Yorkie signaling correlate positively in hepatocellular carcinoma. We show that IIS activates Yorkie in vivo, and that Yorkie plays an important role in the ability of IIS to drive cell proliferation. Interestingly, we also find the converse-that Yorkie signaling activates components of the insulin/TOR pathway. In sum, this crosstalk between IIS and Yorkie leads to coordinated regulation of these two oncogenic pathways.
    Type of Publication: Journal article published
    PubMed ID: 22609549
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