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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Development - 2 Study Section (DEV2)
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Haynes, Susan R
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Cincinnati Children's Hospital Medical Center
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Zandvakili, Arya; Uhl, Juli D; Campbell, Ian et al. (2018) The cis-regulatory logic underlying abdominal Hox-mediated repression versus activation of regulatory elements in Drosophila. Dev Biol :
Zandvakili, Arya; Campbell, Ian; Gutzwiller, Lisa M et al. (2018) Degenerate Pax2 and Senseless binding motifs improve detection of low-affinity sites required for enhancer specificity. PLoS Genet 14:e1007289
Gu, Zirong; Kalambogias, John; Yoshioka, Shin et al. (2017) Control of species-dependent cortico-motoneuronal connections underlying manual dexterity. Science 357:400-404
Wang, Guolun; Gutzwiller, Lisa; Li-Kroeger, David et al. (2017) A Hox complex activates and potentiates the Epidermal Growth Factor signaling pathway to specify Drosophila oenocytes. PLoS Genet 13:e1006910
Uhl, Juli D; Zandvakili, Arya; Gebelein, Brian (2016) A Hox Transcription Factor Collective Binds a Highly Conserved Distal-less cis-Regulatory Module to Generate Robust Transcriptional Outcomes. PLoS Genet 12:e1005981
Zandvakili, Arya; Gebelein, Brian (2016) Mechanisms of Specificity for Hox Factor Activity. J Dev Biol 4:
Gresser, Amy L; Gutzwiller, Lisa M; Gauck, Mackenzie K et al. (2015) Rhomboid Enhancer Activity Defines a Subset of Drosophila Neural Precursors Required for Proper Feeding, Growth and Viability. PLoS One 10:e0134915
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
Bryantsev, Anton L; Duong, Sandy; Brunetti, Tonya M et al. (2012) Extradenticle and homothorax control adult muscle fiber identity in Drosophila. Dev Cell 23:664-73
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

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