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 700-800 ommatidia, or facets, 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 share equivalent functions in the mammalian eye. In particular, the correct distinction of two subtypes of photoreceptors, R3 and R4, requires a precise regulation of the Wnt/Frizzled (Fz)/planar cell polarity (PCP) pathway. Strikingly, the second Wnt-Fz mediated signaling pathway, canonical 2-catenin signaling, causes photoreceptor cell death and reduction of eye size. The Fz receptor and its immediate downstream effector Disheveled (Dsh, Dvl in mammals) are shared between Fz/2-catenin and Fz/PCP signaling but activate distinct effectors pathways downstream of Dsh, and thus correct regulation of Fz-Dsh signaling specificity is critical for normal eye development. The regulation of this signaling specificity is poorly understood. The scope of this application is (1) to define regulatory kinase input at the level of Fz-Dsh mediating the correct and specific signaling outcome, (2) to determine the role of Tyrosine phosphorylation of Dsh in pathway selection, (3) to establish the functional requirements of new transcription factors identified to act in the R3/R4 Fz/PCP- mediated cell fate specification, and (4) to define the role of anaphase promoting complex (APC/C) subunits and a Ubiquitin-like peptide in Fz/PCP signaling and R3/R4 specification.
These Aims are based on exciting preliminary data. A combination of in vivo studies in the eye, and cell culture and biochemical experiments 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 pathway(s) 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 retinal patterning and eye disease, and will also be of medical relevance in other areas, including cancer and stem cell biology.

Public Health Relevance

Wnt/Frizzled-signaling has been implicated in several contexts in eye development and is linked to several eye diseases and, also, it is associated with several forms of cancer. Thus dissecting the regulatory mechanisms of the Wnt/Frizzled pathway is of high medical significance. The information acquired in this proposal will advance our understanding of retinal patterning and photoreceptor cell biology, and will be also of importance for several medical disorders.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013256-14
Application #
8607946
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Neuhold, Lisa
Project Start
2001-02-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
14
Fiscal Year
2014
Total Cost
$305,100
Indirect Cost
$125,100
Name
Icahn School of Medicine at Mount Sinai
Department
Biology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Weber, Ursula; Rodriguez, Estefania; Martignetti, John et al. (2014) Luna, a Drosophila KLF6/KLF7, is maternally required for synchronized nuclear and centrosome cycles in the preblastoderm embryo. PLoS One 9:e96933
Serysheva, Ekatherina; Berhane, Hebist; Grumolato, Luca et al. (2013) Wnk kinases are positive regulators of canonical Wnt/*-catenin signalling. EMBO Rep 14:718-25
Yanfeng, Wang A; Berhane, Hebist; Mola, Marion et al. (2011) Functional dissection of phosphorylation of Disheveled in Drosophila. Dev Biol 360:132-42
Singh, Jaskirat; Yanfeng, Wang A; Grumolato, Luca et al. (2010) Abelson family kinases regulate Frizzled planar cell polarity signaling via Dsh phosphorylation. Genes Dev 24:2157-68
Courbard, Jean-Remy; Djiane, Alexandre; Wu, Jun et al. (2009) The apical/basal-polarity determinant Scribble cooperates with the PCP core factor Stbm/Vang and functions as one of its effectors. Dev Biol 333:67-77
Oishi, Kimihiko; Zhang, Hui; Gault, William J et al. (2009) Phosphatase-defective LEOPARD syndrome mutations in PTPN11 gene have gain-of-function effects during Drosophila development. Hum Mol Genet 18:193-201
Skouloudaki, Kassiani; Puetz, Michael; Simons, Matias et al. (2009) Scribble participates in Hippo signaling and is required for normal zebrafish pronephros development. Proc Natl Acad Sci U S A 106:8579-84
Simons, Matias; Mlodzik, Marek (2008) Planar cell polarity signaling: from fly development to human disease. Annu Rev Genet 42:517-40
Weber, Ursula; Pataki, Csilla; Mihaly, Jozsef et al. (2008) Combinatorial signaling by the Frizzled/PCP and Egfr pathways during planar cell polarity establishment in the Drosophila eye. Dev Biol 316:110-23
Jenny, Andreas; Mlodzik, Marek (2008) Modified vectors for the two-step directional cloning of inverted repeats for RNA interference in Drosophila. Biotechniques 44:335-9

Showing the most recent 10 out of 20 publications