Abstract
1. Fyn, a member of Src-family tyrosine kinases, is implicated in both brain development and adult brain function. Recent studies have identified some Fyn substrates, however, little is known about the transcriptional targets for Fyn mediated signaling pathways. In the present study, we sought to identify targets downstream of Fyn in vivo.
2. We compared genes expressed in adult hippocampi of wild-type and fyn-deficient mice using gene chips containing more than 12,000 genes.
3. The results showed that 559 transcripts were expressed differentially between these mice. Expression of 20 genes including a substantial number of myelin-associated genes was strongly repressed in fyn-deficient mice.
4. Reduced expression of these myelin-associated genes, such as MBP and MOG, in fyn-deficient mice was also confirmed by real-time PCR and northern blotting, arguing that Fyn is important for function and development of oligodendrocytes.
5. Further analysis of the genes that are differently expressed in fyn-deficient mice may shed light on the molecular mechanism by which Fyn regulates adult neural function.
Keywords: tyrosine kinase, gene expression, myelination, adult brain functions
REFERENCES
- Aruga, J., Tohmonda, T., Homma, S., and Mikoshiba, K. (2002). Zic1 promotes the expansion of dorsal neural progenitors in spinal cord by inhibiting neuronal differentiation. Dev. Biol. 244:329-341. [DOI] [PubMed] [Google Scholar]
- Ballenthin, P. A., and Gardinier, M. V. (1996). Myelin/oligodendrocyte glycoprotein is alternatively spliced in humans but not mice.J. Neurosci. Res. 46:271-281. [DOI] [PubMed] [Google Scholar]
- Berwanger, B., Hartmann, O., Bergmann, E., Bernard, S., Nielsen, D., Kause, M., Kartal, A., Flynn, D., Wiedemeyer, R., Schwab, M., Schafer, H., Christiansen, H., and Eilers, M. (2002). Loss of FYN-regulated differentiation and growth arrest pathway in advanced neuroblastoma. Cancer Cell 2:377-386. [DOI] [PubMed] [Google Scholar]
- Bosio, A., Binczek, E., and Stoffel, W. (1996). Molecular cloning and characterization of the mouse CGT gene encoding UDP-galactose ceramide-galactosyltransferase (cerebroside synthetase) Genomics 35:223-226. [DOI] [PubMed] [Google Scholar]
- Brouns, M. R., Matheson, S. F., and Settleman, J. (2001). p190 RhoGAP is the principal Src substrate in brain and regulates axon outgrowth, guidance and fasciculation. Nat. Cell Biol. 3:361-367. [DOI] [PubMed] [Google Scholar]
- Grant, S. G., O'Dell, T. J., Karl, K. A., Stein, P. L., Soriano, P., and Kandel, E. R. (1992). Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice. Science 258:1903-1910. [DOI] [PubMed] [Google Scholar]
- Ikenaka, K., Furuichi, T., Iwasaki, Y., Moriguchi, A., Okano, H., and Mikoshiba, K. (1988). Myelin proteolipid protein gene structure and its regulation of expression in normal and jimpy mutant mice. J. Mol. Biol. 199:587-596. [DOI] [PubMed] [Google Scholar]
- Kim, M., Tezuka, T., Suzuki, Y., Sugano, S., Hirai, M., and Yamamoto, T. (1999). Molecular cloning and characterization of a novel cb1-family gene, cb1-c. Gene 239:145-154. [DOI] [PubMed] [Google Scholar]
- Lipshutz, R. J., Fodor, S. P., Gingeras T. R., and Lockhart, D. J. (2000). High density synthetic oligonucleotide arrays. Nature Genet. 21:20-24. [DOI] [PubMed] [Google Scholar]
- Lowell, C. A., Soriano, P. (1996). Knockouts of Src-family kinases: Stiff bones, wimpy T cells, and bad memories. Gene Dev. 10:1845-1857. [DOI] [PubMed] [Google Scholar]
- Magyar, J. P., Ebensperger, C., Schaeren-Wiemers, N., and Suter, U. (1997). Myelin and lymphocyte protein (MAL/MVP17VIP17) and plasmolipin are members of an extended gene family. Gene 189:269-275. [DOI] [PubMed] [Google Scholar]
- McCallion, A. S., Stewart, G. J., Montague, P., Griffiths, I. R., and Davies, R. W. (1999). Splicing pattern, transcript start distribution, and DNA sequence of the mouse gene (Mobp) encoding myelin-associated oligodendrocytic basic protein. Mol. Cell. Neurosci. 13:229-236. [DOI] [PubMed] [Google Scholar]
- Miyakawa, T., Yagi, T., Watanabe, S., and Niki, H. (1994). Increased fearfulness of Fyn tyrosine kinase deficient mice. Brain Res. Mol. Brain Res. 27: 179-182. [DOI] [PubMed] [Google Scholar]
- Morita, K., Sasaki, H., Fujimoto, K., Furuse, M., and Tsukita, S. (1999). Claudin-11/OSP-based tight junctions of myelin sheaths in brain and Sertoli cells in testis. J. Cell Biol. 145:579-588. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nakazawa, T., Komai, S., Tezuka, T., Hisatsune, C., Umemori, H., Semba, K., Mishina, M., Manabe, T., and Yamamoto, T. (2001). Characterization of Fyn-mediated tyrosine phosphorylation sites on GluR epsilon 2 (NR2B) subunit of the N-methyl-D-aspartate receptor. J. Biol. Chem. 276:693-699. [DOI] [PubMed] [Google Scholar]
- Osterhout, D. J., Wolven. A., Wolf, R. M., Resh, M. D., and Chao, M. V. (1999). Morphological differentiation of oligodendrocytes requires activation of Fyn tyrosine kinase. J. Cell Biol. 145:1209-1218. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Patapoutian, A., Reichardt, L. F., (2001). Trk receptors: Mediators of neurotrophin action. Curr. Opin. Neurobiol. 11:272-280. [DOI] [PubMed] [Google Scholar]
- Pfeiffer, S. E., Warrington, A. E., and Bansal, R. (1993).The oligodenrocyte and its many cellular processes. Trends Cell Biol. 3:191-197. [DOI] [PubMed] [Google Scholar]
- Pierantoni, G. M., Bulfone, A., Pentimalli, F., Fedele, M., Iuliano, R., Santoro, M., Chiariotti, L., Ballabio, A., and Fusco, A. (2002). The homeodomain-interacting protein kinase 2 gene is expressed late in embryogenesis and preferentially in retina, muscle, and neural tissues. Biochem. Biophys. Res. Commun. 25:942-947. [DOI] [PubMed] [Google Scholar]
- Sasaki, Y., Cheng, C., Uchida, Y., Nakajima, O., Ohshima, T., Yagi, T., Taniguchi, M., Nakayama, T., Kishida, R., Kudo, Y., Ohno, S., Nakamura, F., and Goshima, Y. (2002). Fyn and Cdk5 mediate semaphorin-3A signaling, which is involved in regulation of dendrite orientation in cerebral cortex. Neuron 35:907-920. [DOI] [PubMed] [Google Scholar]
- Seiwa, C., Sugiyama, I., Yagi, T., Iguchi, T., and Asou, H. (2000). Fyn tyrosine kinase participates in the compact myelin sheath formation in the central nervous system. Neurosci. Res. 37:21-31. [DOI] [PubMed] [Google Scholar]
- Senzaki, K., Ogawa, M., and Yagi, T. (1999). Proteins of the CNR family are multiple receptors for Reelin. Cell 99:635-647. [DOI] [PubMed] [Google Scholar]
- Shimono, A., Okuda, T., and Kondoh, H. (2002). N-myc-dependent repression of ndr1, a gene identified by direct subtraction of whole mouse embryo cDNAs between wild type and N-myc mutant. Mech. Dev. 83:39-52. [DOI] [PubMed] [Google Scholar]
- Sperber, B. R., Boyle-Wyelination, E. A., Engleka, M. J., Gardue, P. A., Peterson,C., Stein, P. L., Scherer, S. S., and McMorris, F.A. (2001).Aunique role for Fyn in CNS Myelination. J. Neurosci. 21:2039-2047. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Taniike, M., Mohri, I., Eguchi, N., Beuckmann, C. T., Suzuki, K., and Urade, Y. (2002). Perineuronal oligodendrocytes protect against neuronal apoptosis through the production of lipocalin-type prostaglandin D synthase in a genetic demyelinating model. J. Neurosci. 22:4885-4896. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tezuka, T., Umemori, H., Akiyama, T., Nakanishi, S., Yamamoto, T. (1999). PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the N-methyl-D-aspartate receptor subunit NR2A. Proc. Natl. Acad. Sci. USA 96:435-440. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Umemori, H., Sato, S., Yagi, T., Aizawa, S., and Yamamoto, T. (1994) Initial events of myelination involve Fyn tyrosine kinase signaling. Nature 367:572-576. [DOI] [PubMed] [Google Scholar]
- Umemori, H., Kadowaki, Y., Hirosawa, K., Yoshida, Y., Hironaka, K., Okano, H., and Yamamoto, T. (1999). Stimulation of myelin basic protein gene transcription by Fyn tyrosine kinase for myelination. J. Neurosci. 19:1393-1397. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wilkinson, D. G. (2001). Multiple roles of Eph receptors and ephrins in neural development. Nat. Rev. Neurosci. 2:155-164. [DOI] [PubMed] [Google Scholar]
- Wolf,R. M., Wilkes, J. J., Chao, M.V., and Resh, M.D. (2001). Tyrosine phosphorylation of p190 RhoGAP by Fyn regulates oligodendrocyte differentiation. J. Neurobiol. 49:62-78. [DOI] [PubMed] [Google Scholar]
- Yagi, T., Shigetani, Y., Okado, N., Tokunaga, T., Ikawa, Y., and Aizawa, S., (1993). Regional localization of Fyn in adult brain; studies with mice in which fyn gene was replaced by lacZ. Oncogene 8:3343-3351. [PubMed] [Google Scholar]
- Yu, X., and Salter, M. W. (1996). Src, a molecular switch governing gain control of synaptic transmission mediated by N-methyl-D-aspartate receptors. Proc. Natl. Acad. Sci. USA 96:7697-7704. [DOI] [PMC free article] [PubMed] [Google Scholar]
