Laboratory for Molecular Membrane Neuroscience

A reciprocal relationship existing between glia cells and neurons is vital for brain development and the maintenance of the functional neurons. In 1998, we discovered that the survival and morphological development of hippocampal neurons are completely dependent on the non-essential amino acid, L-seine released actively from astroglia. Non-essential amino acid "L-serine" synthesized from glucose in astroglial is "essential" amino acid for neuron development. Addition of L-serine stimulates the synthesis of neuronal membrane lipids including sphingolipids. We have demonstrated that such metabolic neuron-glial relationship is an essential part to the developing and adult brain in vivo.
In 2006, we were succeeded in determining the complete structure of a new type of glucosylated glycolipid, phosphatidylglucoside (PtdGlc) present in lipid rafts in the murine central nervous system. PtdGlc is composed of saturated fatty acyl chains: C18:0 at the sn-1 and C18:0/C20:0 at the sn-2 positions of the glycerol backbone, donating its presence in lipid rafts. PtdGlc is expressed in the astroglial lineage cells, from radial glia to astroglia, in developing mouse brain. The glycolipid is also detectable in the adult stem cells in brain. Very recently, we successfully identified one of metabolites lyso-PtdGlc produced by radial glia cells as bioactive lipid invoved in chemo-repulsion to developing neurons.
We found that membrane glycoprotein with 7-transmembrane domains "BOSS" is localized in lipid rafts of Drosophila nutrient-sensing tissue, the fat body and brain. BOSS mutant shows elevated circulating glucose and lipid levels, an impaired response to nutrient deprivation (starvation). Since humans/mice have GPRC5s (Gprc5b) that share sequence similarity with BOSS, we provide a new insight of conserved glucose and energy-sensing mechanisms through the membrane glycoproteins in the lipid rafts. In fact, we have shown that Gprc5b knockout mice are protected from high-fat diet-induced obesity and insulin resistant.

Research Subjects

• Molecular cellular biology of membrane sphingolipid biosynthesis
• Neuron-astroglia interaction required for neuronal survival and development
• Molecular cellular biology of lipid rafts and complex carbohydrate
• Molecular mechanisms of energy-sensing in multicellular system

Publications

1. Kim YJ, Sano T, Nabetani T, Asano Y, Hirabayashi Y.:
   "Gprc5b activates obesity-associated inflammatory signaling in adipocyte"
   Sci Signal. 2012 Nov 20;5(251):ra85
2. Kohyama-Koganeya, A, Kim YJ, Miura M, Hirabayashi Y.:
   "Drosophila Bride of sevenless (boss) functions as a glucose-responding receptor: loss of boss causes abnormal sugar and lipid metabolism."
   Proc Natl Acad Sci U S A. 105(40), 15328-15333 (2008)
3. Hirabayashi Y, Furuya S.:
   "Roles of l-serine and sphingolipid synthesis in brain development and neuronal survival"
   Prog. Lipid Res. 47(3), 188-203 (2008).
4. Nagatsuka Y, Horibata Y, Yamazaki Y, Kinoshita M, Shinoda Y, Hashikawa T, Koshino H, Nakamura T, Hirabayashi Y.:
   "Phosphatidylglucoside exists as a single molecular species with saturated fatty acyl chains in developing astroglial membranes"
   Biochemistry 45(29), 8742-8750 (2006).
5. Koganeya AK, Sasamura T, Oshima E, Suzuki E, Nishihara S, Ueda R, Hirabayashi Y.:
   "Drosophila glucosylceramide synthase: A negative regulator of cell death mediated by proapoptotic factors."
   J Biol Chem. 279, 35995-36002 (2004)
6. Yoshida, K., Furuya, S., Osuka, S., Mitoma, J., Shinoda, Y., Watanabe, M., Azuma, N., Tanaka, H., Hashikawa, T., Itohara, S., and Hirabayashi, Y.:
   "Targeted disruption of the mouse 3-phosphoglycerate dehydrogenase gene causes severe neurodevelopmental defects and results in embryonic lethality"
   J. Biol. Chem., 279, 3573-3577 (2004).
7. Nagatsuka, Y., Fujiwara, S., Ohshima, E., Ishii, K., Kobayashi, T., Shimizu, K., and Hirabayashi, Y.:
   "Carbohydrate-dependent signaling from the phosphatidylglucoside-based microdomain induces granulocytic differentiation of HL60 cells"
   Proc. Natl. Acad. Sci. USA., 100, 7454-7459 (2003).
8. Yamazaki, M., Yamada, K., Furuya, S., Mitoma, J., Hirabayashi, Y., and Watanabe, M.:
   "3- Phosphoglycerate dehydrogenase (3PGDH), a key enzyme for L-serine biosynthesis, is preferentially expressed in the radial glia/ astrocyte lineage and olfactory ensheathing glia in the mouse brain"
   J. Neuroscience, 21, 7691-7704 (2001).
9. Furuya, S., Tabata, T., Mitoma, J., Yamada, K., Yamasaki, M., Yamamoto, T., Watanabe, M., Kano, M., and Hirabayashi, Y.:
   "L-Serine and glycine serve as major astroglia-derived trophic factors for cerebellar Purkinje neurons"
   Proc. Natl. Acad. Sci. USA, 97, 11528-11533 (2000).
10. Ichikawa, S. and Hirabayashi, Y.:
    "Glucosylceramide synthase and glycosphingolipid synthesis"
    Trends Cell Biol.,(review article)8, 198-202 (1998).