Recognition of sulfated hexosamine upon construction of the nervous system

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We generated mice deficient in N-acetylglucosamine 6-sulfotransferase-1 (GlcNAc6ST-1). These mice exhibited lower activity in lymphocyte homing to lymph nodes compared to wild-type mice, establishing that GlcNAc6ST-1 is involved in synthesis of L-selectin ligand. International collaboration yielded double knockout mice deficient in both GlcNAc6ST-1 and -2. Studies using the double knockout mice revealed that GlcNAc&ST-1 and -2 co-operate in production of L-selectin ligand. GlcNAc6ST-1 was also involved in synthesis of keratan sulfate. Glia scar formation upon brain injury was reduced in GlcNAc6ST-1 knockout mice, indicating that keratan sulfate hinders repair of injured brain through promotion of glia scar formation. Midkine is a heparin-binding growth factor, which promotes growth, survival and migration of target cells. Mice doubly deficient in both midkine and pleiotrophin, another member of the growth factor family, exhibited auditory deficits and female infertility, and was reduced in spontaneous locomotive activity. Using neural precursor cells derived from midkine-deficient mice, we found that midkine promotes growth and survival of neural precursor cells without affecting their differentiation capability. These activities are the basis of promotion of neurogenesis by midkine. The glycosaminoglycan structure required for strong binding to midkine was clarified to be repeated structures composed of chondroitin sulfate E units or heparan sulfate trisulfated units. As midkine receptors, proteoglycans, integrins and low density lipoprotein receptor-related proteins are important, and were proposed to form molecular complex in the presence of midkine. Upon process formation of oligodendrocyte precursor-like cells, neuroglycan C, a part time proteoglycan was also identified as a component of the receptor.