De Novo GMP Synthesis Is Required for Axon Guidance in Drosophila

Abstract

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.

Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity

“…So far, angustmycin A has been mainly employed as an antibiotic and most of the studies on its activity have been conducted in bacteria or other lower organisms where it was shown that guanylates have a key role in several aspects of their biology including sporulation, pathogenicity, and axon guidance. [18][19][20]28,29 A single study performed in mice failed to reveal any immune-suppressive efficacy, however, it showed good tolerability. 31 MMF, an inhibitor of IMPDH enzymes, is currently in clinical use as an immunosuppressant although two recent papers suggested that MMF may possess anti-cancer activities in vivo.…”

“…16,17 Most of the studies on GMPS have been performed in bacteria, yeast, and insects, where GMPS has been shown to have a key role in sporulation, pathogenicity, and axon guidance, respectively. [18][19][20] Mammalian GMPS has been the subject of several studies addressing its unconventional (GMP-unrelated) roles in the regulation of activity of ubiquitin-specific protease 7 (USP7). [21][22][23][24] However, because of the newly revealed importance of guanylate metabolism in control of melanoma cell invasion and tumorigenicity, 8 GMPS emerges as an attractive target for anti-cancer therapy.…”

A Misexpression Screen to Identify Regulators of Drosophila Larval Hemocyte Development

“…This is confirmed by other insertions that display the same phenotype. These included raspberry (EP1519), which has been implicated in the control of axon guidance (Long et al 2006), and Rho signaling (Gregory et al 2007), and as described previously, scb, C3G, and tlk.…”

Zebrafish mutations ingartandpaicsidentify crucial roles for de novo purine synthesis in vertebrate pigmentation and ocular development

“…Perhaps the most well-studied model for the function of the de novo purine synthesis pathway during development comes from work in Drosophila, in which mutations in prat (ppat) (Clark, 1994), ade2 (pfas) (Henikoff et al, 1986b;Johnstone et al, 1985), ade3 (gart) (Henikoff et al, 1986a;Johnstone et al, 1985) and ade5 (paics) (O'Donnell et al, 2000) have been identified, as well as mutations in the GTP pathway components IMPDH (raspberry) and GMP synthase (burgundy) (Johnstone et al, 1985;Long et al, 2006). Each of these de novo pathway mutants shows a subset of developmental defects that have collectively been termed the 'purine syndrome' phenotype (Tiong et al, 1989).…”

“…Purine syndrome defects include a reduction in the red pteridine-derived eye pigments, bristle and leg malformations, small wings, and pupal lethality (Tiong et al, 1989). Additionally, IMPDH and GMP synthase mutants possess defects in R-cell axon pathfinding (Long et al, 2006).…”