Region- and Neuronal Phenotype-specific Expression of NELL2 in the Adult Rat Brain

  • Jeong, Jin Kwon (Department of Biological Sciences, University of Ulsan) ;
  • Kim, Han Rae (Department of Biological Sciences, University of Ulsan) ;
  • Hwang, Seong Mun (Department of Biological Sciences, University of Ulsan) ;
  • Park, Jeong Woo (Department of Biological Sciences, University of Ulsan) ;
  • Lee, Byung Ju (Department of Biological Sciences, University of Ulsan)
  • Received : 2008.02.11
  • Accepted : 2008.04.02
  • Published : 2008.08.31

Abstract

NELL2, a neural tissue-enriched protein, is produced in the embryo, and postembryonically in the mammalian brain, with a broad distribution. Although its synthesis is required for neuronal differentiation in chicks, not much is known about its function in the adult mammalian brain. We investigated the distribution of NELL2 in various regions of the adult rat brain to study its potential functions in brain physiology. Consistent with previous reports, NELL2-immunoreactivity (ir) was found in the cytoplasm of neurons, but not in glial fibrillary acidic protein (GFAP)-positive glial cells. The highest levels of NELL2 were detected in the hippocampus and the cerebellum. Interestingly, in the cerebellar cortex NELL2 was observed only in the GABAergic Purkinje cells not in the excitatory granular cells. In contrast, it was found mainly in the hippocampal dentate gyrus and pyramidal cell layer that contains mainly glutamatergic neurons. In the dentate gyrus, NELL2 was not detected in the GFAP-positive neural precursor cells, but was generally present in mature neurons of the subgranular zone, suggesting a role in this region restricted to mature neurons.

Keywords

Acknowledgement

Supported by : KRF

References

  1. Aihara, K., Kuroda, S., Kanayama, N., Matsuyama, S., Tanizawa, K., and Horie, M. (2003). A neuron-specific EGF family protein, NELL2, promotes survival of neurons through mitogen-activated protein kinases. Brain Res. Mol. Brain Res. 116, 86-93. https://doi.org/10.1016/S0169-328X(03)00256-0
  2. Bastianelli, E. (2003). Distribution of calcium-binding proteins in the cerebellum. Cerebellum 2, 242-262. https://doi.org/10.1080/14734220310022289
  3. Baurle, J., Vogten, H., and Grusser-Cornehls, U. (1998). Course and targets of the calbindin D-28k subpopulation of primary vestibular afferents. J. Comp. Neurol. 402, 111-128. https://doi.org/10.1002/(SICI)1096-9861(19981207)402:1<111::AID-CNE8>3.0.CO;2-1
  4. Bouet, V., Dijk, F., Ijkema-Paassen, J., Wubbels, R.J., van der Want, J.J., and Gramsbergen, A. (2005). Early hypergravity exposure effects calbindin-D28k and inositol-3-phosphate expression in Purkinje cells. Neurosci. Lett. 382, 10-15. https://doi.org/10.1016/j.neulet.2005.02.051
  5. Brager, D.H., Sickel, M.J., and McCarthy, M.M. (2000). Developmental sex differences in calbindin-D(28K) and calretinin immunoreactivity in the neonatal rat hypothalamus. J. Neurobiol. 42, 315-322. https://doi.org/10.1002/(SICI)1097-4695(20000215)42:3<315::AID-NEU3>3.0.CO;2-0
  6. Choi, E.J., Ha, C.M., Choi, J., Kang, S.S., Choi, W.S., Park, S.K., Kim, K., and Lee, B.J. (2001). Low-density cDNA array-coupled to PCR differential display identifies new estrogen-responsive genes during the postnatal differentiation of the rat hypothalamus. Brain Res. Mol. Brain Res. 97, 115-128. https://doi.org/10.1016/S0169-328X(01)00302-3
  7. Christopherson, K.S., Ullian, E.M., Stokes, C.C., Mullowney, C.E., Hell, J.W., Agah, A., Lawler, J., Mosher, D.F., Bornstein, P., and Barres, B.A. (2005). Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120, 421-433. https://doi.org/10.1016/j.cell.2004.12.020
  8. Gabbott, P.L., Somogyi, J., Stewart, M.G., and Hamori, J. (1986). GABA-immunoreactive neurons in the rat cerebellum: a light and electron microscope study. J. Comp. Neurol. 251, 474-490. https://doi.org/10.1002/cne.902510404
  9. Ha, C.M., Choi, J., Choi, E.J., Costa, M.E., Lee, B.J., and Ojeda, S.R. (2008). NELL2, a neuron-specific EGF like protein, is selectively expressed in glutamatergic neurons and contributes to the glutamatergic control of GnRH neurons at puberty. Neuroendocrinology (in press).
  10. Hwang, E.M., Kim, D.G., Lee, B.J., Choi, J., Kim, E., Park, N., Kang, D., Han, J., Choi, W.S., Hong, S.G., et al. (2007). Alternative splicing generates a novel non-secretable cytosolic isoform of NELL2. Biochem. Biophys. Res. Commun. 353, 805-811. https://doi.org/10.1016/j.bbrc.2006.12.115
  11. Ishizaki, Y. (2006). Control of proliferation and differentiation of neural precursor cells: focusing on the developing cerebellum. J. Pharmacol. Sci. 101, 183-188. https://doi.org/10.1254/jphs.CPJ06011X
  12. Kim, H., Ha, C.M., Choi, J., Choi, E.J., Jeon, J., Kim, C., Park, S.K., Kang, S.S., Kim, K., and Lee, B.J. (2002). Ontogeny and the possible function of a novel epidermal growth factor-like repeat domain-containing protein, NELL2, in the rat brain. J. Neurochem. 83, 1389-1400. https://doi.org/10.1046/j.1471-4159.2002.01245.x
  13. Kim, J.G., Nam-Goong, I.S., Yun, C.H., Jeong, J.K., Kim, E.S., Park, J.J., Lee, Y.C., Kim, Y.I., and Lee, B.J. (2006). TTF-1, a homeodomain-containing transcription factor, regulates feeding behavior in the rat hypothalamus. Biochem. Biophys. Res. Commun. 349, 969-975. https://doi.org/10.1016/j.bbrc.2006.08.147
  14. Kuroda, S., and Tanizawa, K. (1999). Involvement of epidermal growth factor-like domain of NELL proteins in the novel proteinprotein interaction with protein kinase C. Biochem. Biophys. Res. Commun. 265, 752-757. https://doi.org/10.1006/bbrc.1999.1753
  15. Kuroda, S., Oyasu, M., Kawakami, M., Kanayama, N., Tanizawa, K., Saito, N., Abe, T., Matsuhashi, S., and Ting, K. (1999). Biochemical characterization and expression analysis of neural thrombospondin-1-like proteins NELL1 and NELL2. Biochem. Biophys. Res. Commun. 265, 79-86. https://doi.org/10.1006/bbrc.1999.1638
  16. Li, R.W., Yu, W., Christie, S., Miralles, C.P., Bai, J., Loturco, J.J., and De Blas, A.L. (2005). Disruption of postsynaptic GABA receptor clusters leads to decreased GABAergic innervation of pyramidal neurons. J. Neurochem. 95, 756-770. https://doi.org/10.1111/j.1471-4159.2005.03426.x
  17. Lin, T.N., Kim, G.M., Chen, J.J., Cheung, W.M., He, Y.Y., and Hsu, C.Y. (2003). Differential regulation of thrombospondin-1 and thrombospondin-2 after focal cerebral ischemia/reperfusion. Stroke 34, 177-186. https://doi.org/10.1161/01.STR.0000047100.84604.BA
  18. Matsuhashi, S., Noji, S., Koyama, E., Myokai, F., Ohuchi, H., Taniguchi, S., and Hori, K. (1995). New gene, nel, encoding a M(r) 93 K protein with EGF-like repeats is strongly expressed in neural tissues of early stage chick embryos. Dev. Dyn. 203, 212-222. https://doi.org/10.1002/aja.1002030209
  19. Matsuyama, S., Aihara, K., Nishino, N., Takeda, S., Tanizawa, K., Kuroda, S., and Horie, M. (2004). Enhanced long-term potentiation in vivo in dentate gyrus of NELL2-deficient mice. Neuroreport 15, 417-420. https://doi.org/10.1097/00001756-200403010-00007
  20. Matsuyama, S., Doe, N., Kurihara, N., Tanizawa, K., Kuroda, S., Iso, H., and Horie, M. (2005). Spatial learning of mice lacking a neuron- specific epidermal growth factor family protein, NELL2. J. Pharmacol. Sci. 98, 239-243. https://doi.org/10.1254/jphs.FP0050211
  21. McCarthy, M.M. (1995). Frank A. Beach Award. Functional significance of steroid modulation of GABAergic neurotransmission: analysis at the behavioral, cellular, and molecular levels. Horm. Behav, 29, 131-140. https://doi.org/10.1006/hbeh.1995.1010
  22. Mello, C.V., Jarvis, E.D., Denisenko, N., and Rivas, M. (1997). Isolation of song-regulated genes in the brain of songbirds. Methods Mol. Biol. 85, 205-217.
  23. Ming, G.L., and Song, H. (2005). Adult neurogenesis in the mammalian central nervous system. Annu. Rev. Neurosci. 28, 223-250. https://doi.org/10.1146/annurev.neuro.28.051804.101459
  24. Moon, I.S., Cho, S.J., Jin, I., and Walikonis, R. (2007). A simple method for combined fluorescence in situ hybridization and immunocytochemistry. Mol. Cells 24, 76-82.
  25. Nelson, B.R., Matsuhashi, S., and Lefcort, F. (2002). Restricted neural epidermal growth factor-like like 2 (NELL2) expression during muscle and neuronal differentiation. Mech. Dev. 119 (Suppl. 1), S11-19. https://doi.org/10.1016/S0925-4773(03)00084-4
  26. Nelson, B.R., Claes, K., Todd, V., Chaverra, M., and Lefcort, F. (2004). NELL2 promotes motor and sensory neuron differentiation and stimulates mitogenesis in DRG in vivo. Dev. Biol. 270, 322-335. https://doi.org/10.1016/j.ydbio.2004.03.004
  27. Oyasu, M., Kuroda, S., Nakashita, M., Fujimiya, M., Kikkawa, U., and Saito, N. (2000). Immunocytochemical localization of a neuron- specific thrombospondin-1-like protein, NELL2: light and electron microscopic studies in the rat brain. Brain Res. Mol. Brain Res. 76, 151-160. https://doi.org/10.1016/S0169-328X(99)00342-3
  28. Pinaud, R., Velho, T.A., Jeong, J.K., Tremere, L.A., Leao, R.M., von Gersdorff, H., and Mello, C.V. (2004). GABAergic neurons participate in the brain's response to birdsong auditory stimulation. Eur. J. Neurosci. 20, 1318-1330. https://doi.org/10.1111/j.1460-9568.2004.03585.x
  29. Steiner, B., Klempin, F., Wang, L., Kott, M., Kettenmann, H., and Kempermann, G. (2006). Type-2 cells as link between glial and neuronal lineage in adult hippocampal neurogenesis. Glia 54, 805-814. https://doi.org/10.1002/glia.20407
  30. Watanabe, T.K., Katagiri, T., Suzuki, M., Shimizu, F., Fujiwara, T., Kanemoto, N., Nakamura, Y., Hirai, Y., Maekawa, H., and Takahashi, E. (1996). Cloning and characterization of two novel human cDNAs (NELL1 and NELL2) encoding proteins with six EGF-like repeats. Genomics 38, 273-276. https://doi.org/10.1006/geno.1996.0628