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The Journal of Neuroscience, September 1, 2000, 20(17):6540-6550

Netrin-G1: a Novel Glycosyl Phosphatidylinositol-Linked Mammalian Netrin That Is Functionally Divergent from Classical Netrins

Toshiaki Nakashiba^{1, 2}, Toshio Ikeda¹, Sachiko Nishimura^{1, 2}, Kei Tashiro³, Tasuku Honjo⁴, Joseph G. Culotti⁵, and Shigeyoshi Itohara¹

¹ Laboratory for Behavioral Genetics, Brain Science Institute, RIKEN, Hirosawa, Wako, Saitama 351-0198, Japan, ² Institute for Virus Research, ³ Center for Molecular Biology and Genetics, ⁴ Department of Medical Chemistry, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan, and ⁵ Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada

UNC-6/netrins compose a small phylogenetically conserved family of proteins that act as axon guidance cues. With a signal sequence trap method, we isolated a cDNA encoding a novel member of the UNC-6/netrin family, which we named netrin-G1. Unlike classical netrins, netrin-G1 consists of at least six isoforms of which five were predominantly anchored to the plasma membrane via glycosyl phosphatidyl-inositol linkages. Netrin-G1 transcripts were first detected in midbrain and hindbrain regions by embryonic day 12 and reached highest levels at perinatal stages in various brain regions, including olfactory bulb mitral cells, thalamus, and deep cerebellar nuclei. Its expression was primarily restricted to the CNS. Interestingly, netrin-G1 proteins did not show appreciable affinity to any netrin receptor examined. Unlike netrin-1, a secreted form of netrin-G1 consistently failed to attract circumferentially growing axons from the cerebellar plate. Our findings suggest that netrin-G1 and its putative receptors have coevolved independently from the classical netrins. The expression pattern of netrin-G1 and its predicted neuronal membrane localization suggest it may also have novel signaling functions in nervous system development.

Key words: netrin; GPI-linkage; glycosyl phosphatidylinositol; axon guidance; receptor; signal sequence trap; UNC-6; mouse; isoform; alternative splicing; CNS

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20176540-11$05.00/0

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