Anterograde Jelly belly and Alk Receptor Tyrosine Kinase Signaling Mediates Retinal Axon Targeting in Drosophila

Abstract

Anaplastic lymphoma kinase (Alk) has been proposed to regulate neuronal development based on its expression pattern in vertebrates and invertebrates; however, its function in vivo is unknown. We demonstrate that Alk and its ligand Jelly belly (Jeb) play a central role as an anterograde signaling pathway mediating neuronal circuit assembly in the Drosophila visual system. Alk is expressed and required in target neurons in the optic lobe, whereas Jeb is primarily generated by photoreceptor axons and functions in the eye to control target selection of R1-R6 axons in the lamina and R8 axons in the medulla. Impaired Jeb/Alk function affects layer-specific expression of three cell-adhesion molecules, Dumbfounded/Kirre, Roughest/IrreC, and Flamingo, in the medulla. Moreover, loss of flamingo in target neurons causes some R8-axon targeting errors observed in Jeb and Alk mosaic animals. Together, these findings suggest that Jeb/Alk signaling helps R-cell axons to shape their environment for target recognition.

Dependence receptors: a new paradigm in cell signaling and cancer therapy

“…Interestingly, the level of neuronal cell death (measured by active caspase 3 level) in the ALK expressing optic lobe medulla increases in mutants lacking an expression of jeb. Moreover, caspase-dependent neuronal apoptosis dramatically decreases in mutants overexpressing jeb (Bazigou et al, 2007). These results suggest that ALK could have a role in the physiological negative selection of neurons shaping the optic lobe in the Drosophila nervous system by favoring apoptosis in the absence of the ALK ligand.…”

ALK is a Novel Dependence Receptor: Potential Implications in Development and Cancer

“…Moreover, caspase-dependent neuronal apoptosis dramatically decreases in mutants overexpressing jeb. 44 These results suggest ALK could play a role in the physiological negative selection of neurons shaping the optic lobe in the Drosophila nervous system, by favoring apoptosis in the absence of the ALK ligand. These in vivo in vivo observations provide a strong support to our classification of ALK as a dependence receptor.…”

“…ALK is expressed and required in target neurons in the optic lobe, whereas jeb is primarily generated by photoreceptor axons and functions in the eye to control target selection of specific photoreceptor cell axons. 44 Interestingly, the authors pointed out that the level of neuronal cell death (measured by active caspase 3 expression) in the optic lobe medulla, an area in which ALK is expressed, increases in mutants lacking expression of jeb. Moreover, caspase-dependent neuronal apoptosis dramatically decreases in mutants overexpressing jeb.…”

“…18 Together, these findings suggest that jeb/ ALK signaling helps photoreceptor cell axons to shape their environment for target neuron recognition. 44 It should also be noted that an ALK homologue has been identified in C. elegans. It is expressed at low levels in the nervous system and is proposed to regulate synapse differentiation at neuromuscular junctions.…”

A Mosaic Genetic Screen for Drosophila Neoplastic Tumor Suppressor Genes Based on Defective Pupation

“…We also used the amensiac-GAL4 line (Caldwell et al 2005) to drive ring gland expression of three constructs that cause neoplastic transformation of disc tissue (an avl RNA interference construct, an activated form of atypical protein kinase C, and a truncated version of Crumbs; Lu and Bilder 2005) but observed no alterations in pupation or adult viability (data not shown). Finally, we crossed known neoplastic TSG mutations to flies carrying the ey3.5FLP/cell lethal system, which utilizes an eyeless promoter fragment that is restricted to the eye disc and shows no expression in the ring gland (Bazigou et al 2007;supplemental Figure S1, I and J). Although recombination driven by ey3.5FLP was variable and often incomplete, larvae that failed to pupate contained eye discs with neoplastic phenotypes resembling those caused by the eyFLP-cell lethal system (Figure 2, H-J).…”