| Budget Amount *help |
¥14,100,000 (Direct Cost: ¥14,100,000)
Fiscal Year 2003: ¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2002: ¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2001: ¥6,300,000 (Direct Cost: ¥6,300,000)
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| Research Abstract |
We identified novel members of the UNC-6/netrin family, namely netrin-G1 and netrin-G2. Unlike classic netrins these molecules anchor to the plasma membrane via glycosyl phosphatidyl-inositol linkages and do not bind to receptors for classic netrins. Thus, these proteins likely have roles distinct from those of classic netrin members. Netnn-G1 and -G2 are expressed in distinct brain regions in a mutually exclusive manner, indicating their non-redundant roles in the brain. As a way to analyze functions of these molecules, we cultured thalamic and cortical neurons on immobilized recombinant nertin-G1 and netrin-G2. We observed extension of neuritis on these molecules. Conversely, immorbilized anti-netrin-G1 antibodies altered shapes of cultured thalamic neurons. These results suggest that netrin-Gs provide short-range cues for axonal and/or dendritic behavior through bi-directional signaling. To further study the functions of these proteins in vivo, we generated mice devoid of either netrin-G1 or -G2. These mice develop normaly and are fertile. We analyzed these mice by histologic, electrophysiologic, and behavioral methods. Although these mice did not show gross anatomical abnormalities, they showed characteristic behavioral abnormalities. The netrin-G1 deficient mice showed deficits in sensory systems, and netrin-G2 deficient mice showed deficits in higher cognitive functions. Furthermore, electrophysiogical experiments revealed a decrease in NMDA receptor/AMPA receptor activity retio, in a pathway specific manner. Taken together, the data suggest that these molecules have important roles in neuronal network formation in mice.
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