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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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          Most cited references 111

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          The hippo signaling pathway in development and cancer.

           Duojia Pan (2010)
          First discovered in Drosophila, the Hippo signaling pathway is a conserved regulator of organ size. Central to this pathway is a kinase cascade leading from the tumor suppressor Hippo (Mst1 and Mst2 in mammals) to the oncoprotein Yki (YAP and TAZ in mammals), a transcriptional coactivator of target genes involved in cell proliferation and survival. Here, I review recent progress in elucidating the molecular mechanism and physiological function of Hippo signaling in Drosophila and mammals. These studies suggest that the core Hippo kinase cascade integrates multiple upstream inputs, enabling dynamic regulation of tissue homeostasis in animal development and physiology. Copyright © 2010 Elsevier Inc. All rights reserved.
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            A gene complex controlling segmentation in Drosophila.

             Edwin 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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              The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP.

              Coordination between cell proliferation and cell death is essential to maintain homeostasis in multicellular organisms. In Drosophila, these two processes are regulated by a pathway involving the Ste20-like kinase Hippo (Hpo) and the NDR family kinase Warts (Wts; also called Lats). Hpo phosphorylates and activates Wts, which in turn, through unknown mechanisms, negatively regulates the transcription of cell-cycle and cell-death regulators such as cycE and diap1. Here we identify Yorkie (Yki), the Drosophila ortholog of the mammalian transcriptional coactivator yes-associated protein (YAP), as a missing link between Wts and transcriptional regulation. Yki is required for normal tissue growth and diap1 transcription and is phosphorylated and inactivated by Wts. Overexpression of yki phenocopies loss-of-function mutations of hpo or wts, including elevated transcription of cycE and diap1, increased proliferation, defective apoptosis, and tissue overgrowth. Thus, Yki is a critical target of the Wts/Lats protein kinase and a potential oncogene.
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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
                Affiliations
                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
                © 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.

                Page count
                Figures: 7, Tables: 0, Pages: 31
                Product
                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

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