Vol. 14, Issue 1, 241-250, January 2003

Deregulation of the Egfr/Ras Signaling Pathway Induces Age-related Brain Degeneration in the Drosophila Mutant vap

José A. Botella,^* Doris Kretzschmar,^* Claudia Kiermayer,^* Pascale Feldmann,^§ David A. Hughes,^§¶ and Stephan Schneuwly^*

 ^*Lehrstuhl für Entwicklungsbiologie, Universität Regensburg, 93040 Regensburg, Germany; and  ^§CRC Centre for Cell and Molecular Biology, Institute of Cancer Research, London SW3 6JB, United Kingdom

Ras signaling has been shown to play an important role in promoting cell survival in many different tissues. Here we show that upregulation of Ras activity in adult Drosophila neurons induces neuronal cell death, as evident from the phenotype of vacuolar peduncle (vap) mutants defective in the Drosophila RasGAP gene, which encodes a Ras GTPase-activating protein. These mutants show age-related brain degeneration that is dependent on activation of the EGF receptor signaling pathway in adult neurons, leading to autophagic cell death (cell death type 2). These results provide the first evidence for a requirement of Egf receptor activity in differentiated adult Drosophila neurons and show that a delicate balance of Ras activity is essential for the survival of adult neurons.