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.
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.
|Humphries, Ashley Ceinwen; Mlodzik, Marek (2018) From instruction to output: Wnt/PCP signaling in development and cancer. Curr Opin Cell Biol 51:110-116|
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|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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