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      Cell-Autonomous and Non-cell-autonomous Function of Hox Genes Specify Segmental Neuroblast Identity in the Gnathal Region of the Embryonic CNS in Drosophila

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          Abstract

          During central nervous system (CNS) development neural stem cells (Neuroblasts, NBs) have to acquire an identity appropriate to their location. In thoracic and abdominal segments of Drosophila, the expression pattern of Bithorax-Complex Hox genes is known to specify the segmental identity of NBs prior to their delamination from the neuroectoderm. Compared to the thoracic, ground state segmental units in the head region are derived to different degrees, and the precise mechanism of segmental specification of NBs in this region is still unclear. We identified and characterized a set of serially homologous NB-lineages in the gnathal segments and used one of them (NB6-4 lineage) as a model to investigate the mechanism conferring segment-specific identities to gnathal NBs. We show that NB6-4 is primarily determined by the cell-autonomous function of the Hox gene Deformed ( Dfd). Interestingly, however, it also requires a non-cell-autonomous function of labial and Antennapedia that are expressed in adjacent anterior or posterior compartments. We identify the secreted molecule Amalgam (Ama) as a downstream target of the Antennapedia-Complex Hox genes labial, Dfd, Sex combs reduced and Antennapedia. In conjunction with its receptor Neurotactin (Nrt) and the effector kinase Abelson tyrosine kinase (Abl), Ama is necessary in parallel to the cell-autonomous Dfd pathway for the correct specification of the maxillary identity of NB6-4. Both pathways repress CyclinE ( CycE) and loss of function of either of these pathways leads to a partial transformation (40%), whereas simultaneous mutation of both pathways leads to a complete transformation (100%) of NB6-4 segmental identity. Finally, we provide genetic evidences, that the Ama-Nrt-Abl-pathway regulates CycE expression by altering the function of the Hippo effector Yorkie in embryonic NBs. The disclosure of a non-cell-autonomous influence of Hox genes on neural stem cells provides new insight into the process of segmental patterning in the developing CNS.

          Author Summary

          The central nervous system (CNS) needs to be subdivided into functionally specified regions. In the developing CNS of Drosophila, each neural stem cell, called neuroblasts (NB), acquires a unique identity according to its anterior-posterior and dorso-ventral position to generate a specific cell lineage. Along the anterior-posterior body axis, Hox genes of the Bithorax-Complex convey segmental identities to NBs in the trunk segments. In the derived gnathal and brain segments, the mechanisms specifying segmental NB identities are largely unknown. We investigated the role of Hox genes of the Antennapedia-Complex in the gnathal CNS. In addition to cell-autonomous Hox gene function, we unexpectedly uncovered a parallel non-cell-autonomous pathway in mediating segmental specification of embryonic NBs in gnathal segments. Both pathways restrict the expression of the cell cycle gene CyclinE, ensuring the proper specification of a glial cell lineage. Whereas the Hox gene Deformed mediates this cell-autonomously, labial and Antennapedia influence the identity via transcriptional regulation of the secreted molecule Amalgam (and its downstream pathway) in a non-cell-autonomous manner. These findings shed new light on the role of the highly conserved Hox genes during segmental patterning of neural stem cells in the CNS.

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          A gene complex controlling segmentation in Drosophila.

          E B Lewis (1978)
          The bithorax gene complex in Drosophila contains a minimum of eight genes that seem to code for substances controlling levels of thoracic and abdominal development. The state of repression of at least four of these genes is controlled by cis-regulatory elements and a separate locus (Polycomb) seems to code for a repressor of the complex. The wild-type and mutant segmentation patterns are consistent with an antero-posterior gradient in repressor concentration along the embryo and a proximo-distal gradient along the chromosome in the affinities for repressor of each gene's cis-regulatory element.
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            Hippo signaling: growth control and beyond.

            The Hippo pathway has emerged as a conserved signaling pathway that is essential for the proper regulation of organ growth in Drosophila and vertebrates. Although the mechanisms of signal transduction of the core kinases Hippo/Mst and Warts/Lats are relatively well understood, less is known about the upstream inputs of the pathway and about the downstream cellular and developmental outputs. Here, we review recently discovered mechanisms that contribute to the dynamic regulation of Hippo signaling during Drosophila and vertebrate development. We also discuss the expanding diversity of Hippo signaling functions during development, discoveries that shed light on a complex regulatory system and provide exciting new insights into the elusive mechanisms that regulate organ growth and regeneration.
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              Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway

              YAP (Yes-associated protein) is a transcription co-activator in the Hippo tumor suppressor pathway and controls cell growth, tissue homeostasis, and organ size. YAP is inhibited by the kinase Lats, which phosphorylates YAP to induce its cytoplasmic localization and proteasomal degradation. YAP induces gene expression by binding to the TEAD family transcription factors. Dysregulation of the Hippo-YAP pathway is frequently observed in human cancers. Here we show that cellular energy stress induces YAP phosphorylation, in part due to AMPK-dependent Lats activation, thereby inhibiting YAP activity. Moreover, AMPK directly phosphorylates YAP S94, a residue essential for the interaction with TEAD, thus disrupting the YAP-TEAD interaction. AMPK-induced YAP inhibition can suppress oncogenic transformation of Lats-null cells with high YAP activity. Our study establishes a molecular mechanism and functional significance of AMPK in linking cellular energy status to the Hippo-YAP pathway.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, CA USA )
                1553-7390
                1553-7404
                25 March 2016
                March 2016
                : 12
                : 3
                : e1005961
                Affiliations
                [001]Institute of Genetics, University of Mainz, Mainz, Germany
                New York University, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: CB HB GMT. Performed the experiments: HB SR. Analyzed the data: HB CB GMT. Wrote the paper: HB CB GMT.

                Article
                PGENETICS-D-15-02317
                10.1371/journal.pgen.1005961
                4807829
                27015425
                7932fff4-5b9d-4953-bf9a-b3725441f86c
                © 2016 Becker et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 17 September 2015
                : 4 March 2016
                Page count
                Figures: 7, Tables: 0, Pages: 31
                Funding
                This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG, URL: http://www.dfg.de) to GMT (TE 130/9-3; GRK 1044-A1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Genetics
                Gene Expression
                Biology and Life Sciences
                Anatomy
                Nervous System
                Central Nervous System
                Medicine and Health Sciences
                Anatomy
                Nervous System
                Central Nervous System
                Biology and Life Sciences
                Genetics
                Phenotypes
                Research and Analysis Methods
                Model Organisms
                Animal Models
                Drosophila Melanogaster
                Biology and Life Sciences
                Organisms
                Animals
                Invertebrates
                Arthropoda
                Insects
                Drosophila
                Drosophila Melanogaster
                Biology and Life Sciences
                Genetics
                Gene Expression
                Gene Regulation
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Cell Nucleus
                Nuclear Bodies
                Biology and Life Sciences
                Developmental Biology
                Embryology
                Embryos
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Neurons
                Biology and Life Sciences
                Neuroscience
                Cellular Neuroscience
                Neurons
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

                Genetics
                Genetics

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