Mora, N., Almudi, I., Alsina, B., Corominas, M., and Serras, F. (2013) The Beta-amyloid protein precursor like (Appl) is a Ras1/MAPK regulated gene required for axonal targeting in Drosophila photoreceptor neurons. The Journal of cell biology. 126(1):53-59.
In a genome wide expression profile search for genes required for Drosophila R7 photoreceptor development we found Appl, the ortholog of human APP and a key factor in the pathogenesis of Alzheimer's disease. We analyzed Appl expression in the eye imaginal disc and found that is highly accumulated in R7 photoreceptor cells. The R7 photoreceptor
is responsible for UV light detection. To explore the link between high expression of Appl and R7 function, we have analyzed
Appl null mutants and found reduced preference for UV light, likely due to mistargeted R7 axons. Moreover, axon mistargeting and
inappropriate light discrimination are enhanced in combination with neurotactin mutants. R7 differentiation is triggered by
the inductive interaction between R8 and R7 precursors, which results in a burst of Ras1/MAPK activated by the tyrosine kinase
receptor Sevenless. Thus, we have studied whether Ras1/MAPK is responsible for the high Appl expression. Inhibition of Ras1 signaling leads to reduced Appl expression, whereas constitutive activation drives ectopic Appl expression. We show that Appl is directly regulated by the Ras/MAPK pathway through a mechanism mediated by PntP2, an ETS transcription factor that specifically
binds ETS sites in the Appl regulatory region. Also, the zebrafish appb expression increased after ectopic fgfr activation in the neural tube of zebrafish embryos, suggesting a conserved regulatory mechanism.