How cells interpret positional information to properly differentiate and form distinct tissues and organs is a fundamental problem in developmental biology. In the nervous system, for example, numerous neuronal subtypes and sensory organs form at precisely defined positions. The long-term goal of this proposal is to understand how anterior- posterior positional information provided by Hox transcription factors is combined with neuronal differentiation pathways to dictate the type, number, and location of different neurons and sensory organs in the body. Using Drosophila as a model organism, we are focused on understanding how a specific Hox factor, Abdominal-A (Abd-A), modulates sensory organ formation by activating rhomboid (rho). rho encodes a protease that processes an epidermal growth factor (EGF) ligand to induce additional neurons and a set of hepatocyte-like cells. Through bioinformatics and transgenic reporter assays, we identified two Hox-regulated rho enhancers expressed in a specific subset of abdominal sensory neurons. The biochemical and genetic characterization of a conserved enhancer region uncovered a novel mechanism used by Hox factors and their conserved co-factors Extradenticle (Exd) and Homothorax (Hth) to stimulate gene expression: Abd- A antagonizes transcriptional repression by Senseless (Sens), a neuronal zinc finger protein, through direct competition for DNA binding sites. Sens and its vertebrate homologues Growth factor independence-1 (Gfi1) are critical regulators of sensory organ development in both the fly and mouse. We hypothesize that Hox-Sens antagonism is a general mechanism of gene regulation. This hypothesis as well as the identification of other Hox-neuronal transcription factor interactions will be tested in the following aims: 1) Determine the mechanisms used by Abd-A to stimulate rho, 2) Test the role of Hox- Sens competition in the regulation of gene expression, and 3) Identify additional neuronal inputs that regulate rho in ch organ SOP cells. These experiments take advantage of genetic tools available in Drosophila, which unlike in the vertebrate, contain a single set of non-redundant Hox factors. In addition to controlling neuronal development, the Hox, Exd, Hth, and Sens vertebrate homologues all regulate blood cell formation and have been implicated in leukemia. Thus, the Hox and Sens/Gfi1 molecular mechanisms uncovered in this grant are relevant to human development and disease. Public Health Relevance: We have identified two factors that regulate nervous and blood system development. This grant is focused on how these factors function to specify sensory organs using the fruit fly as a model system. As both factors have been implicated in leukemia, our studies are likely to shed new insight into both Human development and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM079428-05
Application #
8230731
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Hoodbhoy, Tanya
Project Start
2008-04-01
Project End
2013-08-08
Budget Start
2012-03-01
Budget End
2013-08-08
Support Year
5
Fiscal Year
2012
Total Cost
$279,329
Indirect Cost
$93,110
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Velu, Chinavenmeni S; Chaubey, Aditya; Phelan, James D et al. (2014) Therapeutic antagonists of microRNAs deplete leukemia-initiating cell activity. J Clin Invest 124:222-36
Fujioka, Miki; Gebelein, Brian; Cofer, Zenobia C et al. (2012) Engrailed cooperates directly with Extradenticle and Homothorax on a distinct class of homeodomain binding sites to repress sloppy paired. Dev Biol 366:382-92
Charlton-Perkins, Mark; Whitaker, S Leigh; Fei, Yueyang et al. (2011) Prospero and Pax2 combinatorially control neural cell fate decisions by modulating Ras- and Notch-dependent signaling. Neural Dev 6:20
Johnston Jr, Robert J; Otake, Yoshiaki; Sood, Pranidhi et al. (2011) Interlocked feedforward loops control cell-type-specific Rhodopsin expression in the Drosophila eye. Cell 145:956-68
Gutzwiller, Lisa M; Witt, Lorraine M; Gresser, Amy L et al. (2010) Proneural and abdominal Hox inputs synergize to promote sensory organ formation in the Drosophila abdomen. Dev Biol 348:231-43
Uhl, Juli D; Cook, Tiffany A; Gebelein, Brian (2010) Comparing anterior and posterior Hox complex formation reveals guidelines for predicting cis-regulatory elements. Dev Biol 343:154-66
Witt, Lorraine M; Gutzwiller, Lisa M; Gresser, Amy L et al. (2010) Atonal, Senseless, and Abdominal-A regulate rhomboid enhancer activity in abdominal sensory organ precursors. Dev Biol 344:1060-70
Lomberk, Gwen A; Imoto, Issei; Gebelein, Brian et al. (2010) Conservation of the TGFbeta/Labial homeobox signaling loop in endoderm-derived cells between Drosophila and mammals. Pancreatology 10:74-84
Li-Kroeger, David; Witt, Lorraine M; Grimes, H Leighton et al. (2008) Hox and senseless antagonism functions as a molecular switch to regulate EGF secretion in the Drosophila PNS. Dev Cell 15:298-308
Gebelein, Brian (2008) The control of EGF signaling and cell fate in the Drosophila abdomen. Fly (Austin) 2:257-8

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