The function of the visual system is to form images in the brain. Correct specification and patterning of the photoreceptor neurons within the retina are a prerequisite for precise retinotopic axonal projections and image formation. The Drosophila eye serves as paradigm for many aspects of eye development, retinal biology and disease. The Drosophila retina is composed of a stereo-typed array of about 800 ommatidia, or unit eyes, each containing a precise arrangement of 8 photoreceptor neurons. The establishment of this precise arrangement requires the interplay of several signaling pathways and transcription factors, all of which are conserved and largely share equivalent functions in the mammalian eye. The correct specification of two of the photoreceptors, R3 and R4, requires an interplay of the Wnt/Frizzled (Fz)/planar cell polarity (PCP) and Notch signaling pathways. Strikingly, the second Fz mediated pathway, canonical (?-Catenin (Cat) signaling, causes photoreceptor cell death and reduction of eye size. As the Fz receptor and (at least) one effector (Dsh) are shared between Fz/|?-Cat and Fz/PCP signaling activating distinct effectors downstream of Dsh, correct regulation of signaling specificity is very critical for normal eye development. The regulation of this signaling specificity is only poorly understood. The scope of this application is to define the sequence elements with the Fz receptor that mediate the specific signaling outcome, and to define the respective modifications on the Dsh protein that distinguish between the Fz/|?-Cat and Fz/PCP pathways. Similarly, we will determine the cross-regulatory interactions between Fz/PCP and Notch signaling. A combination of cell culture and biochemical experiments and in vivo studies in the eye will be utilized to achieve these goals. In the human eye, Fz signaling is associated with diseases like Familial Exudative Vitreoretinopathy (FEVR) and the Norrie Disease. Several components of the Fz and Notch pathways are also critically linked to cancer and are associated with stem cell biology. Thus the information acquired in this application will advance our understanding of photoreceptor specification and eye diseases, and will also be of medical relevance in other areas, including stem cell biology. ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY013256-06
Application #
7038433
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Mariani, Andrew P
Project Start
2001-02-01
Project End
2011-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
6
Fiscal Year
2006
Total Cost
$423,750
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Biology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Humphries, Ashley Ceinwen; Mlodzik, Marek (2018) From instruction to output: Wnt/PCP signaling in development and cancer. Curr Opin Cell Biol 51:110-116
Collu, Giovanna M; Jenny, Andreas; Gaengel, Konstantin et al. (2018) Prickle is phosphorylated by Nemo and targeted for degradation to maintain Prickle/Spiny-legs isoform balance during planar cell polarity establishment. PLoS Genet 14:e1007391
Haider, Afreen; Wei, Yu-Chen; Lim, Koini et al. (2018) PCYT1A Regulates Phosphatidylcholine Homeostasis from the Inner Nuclear Membrane in Response to Membrane Stored Curvature Elastic Stress. Dev Cell 45:481-495.e8
Bigenzahn, Johannes W; Collu, Giovanna M; Kartnig, Felix et al. (2018) LZTR1 is a regulator of RAS ubiquitination and signaling. Science 362:1171-1177
Bala Tannan, Neeta; Collu, Giovanna; Humphries, Ashley C et al. (2018) AKAP200 promotes Notch stability by protecting it from Cbl/lysosome-mediated degradation in Drosophila melanogaster. PLoS Genet 14:e1007153
Wu, Jun; Mlodzik, Marek (2017) Wnt/PCP Instructions for Cilia in Left-Right Asymmetry. Dev Cell 40:423-424
Weber, Ursula; Mlodzik, Marek (2017) APC/CFzr/Cdh1-Dependent Regulation of Planar Cell Polarity Establishment via Nek2 Kinase Acting on Dishevelled. Dev Cell 40:53-66
Carvajal-Gonzalez, Jose Maria; Mulero-Navarro, Sonia; Mlodzik, Marek (2016) Centriole positioning in epithelial cells and its intimate relationship with planar cell polarity. Bioessays 38:1234-1245
Carvajal-Gonzalez, Jose Maria; Mulero-Navarro, Sonia; Smith, Michael et al. (2016) A Novel Frizzled-Based Screening Tool Identifies Genetic Modifiers of Planar Cell Polarity in Drosophila Wings. G3 (Bethesda) 6:3963-3973
Mlodzik, Marek (2016) The Dishevelled Protein Family: Still Rather a Mystery After Over 20 Years of Molecular Studies. Curr Top Dev Biol 117:75-91

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