Originally published as Genetics Published Articles Ahead of Print on December 1, 2005.

Genetics, Vol. 172, 1633-1642, March 2006, Copyright © 2006
doi:10.1534/genetics.105.042911

De Novo GMP Synthesis Is Required for Axon Guidance in Drosophila

Hong Long, Scott Cameron, Li Yu and Yong Rao1

McGill Centre for Research in Neuroscience and Department of Neurology and Neurosurgery, McGill University Health Centre, Montreal, Quebec H3G 1A4, Canada

1 Corresponding author: Centre for Research in Neuroscience, Montreal General Hospital Research Institute, Room L7-136, 1650 Cedar Ave., Montreal, QC H3G 1A4, Canada.
E-mail: yong.rao{at}mcgill.ca

Guanine nucleotides are key players in mediating growth-cone signaling during neural development. The supply of cellular guanine nucleotides in animals can be achieved via the de novo synthesis and salvage pathways. The de novo synthesis of guanine nucleotides is required for lymphocyte proliferation in animals. Whether the de novo synthesis pathway is essential for any other cellular processes, however, remains unknown. In a search for genes required for the establishment of neuronal connectivity in the fly visual system, we identify the burgundy (bur) gene as an essential player in photoreceptor axon guidance. The bur gene encodes the only GMP synthetase in Drosophila that catalyzes the final reaction of de novo GMP synthesis. Loss of bur causes severe defects in axonal fasciculation, retinotopy, and growth-cone morphology, but does not affect photoreceptor differentiation or retinal patterning. Similar defects were observed when the raspberry (ras) gene, encoding for inosine monophosphate dehydrogenase catalyzing the IMP-to-XMP conversion in GMP de novo synthesis, was mutated. Our study thus provides the first in vivo evidence to support an essential and specific role for de novo synthesis of guanine nucleotides in axon guidance.