Hisashi Umemori M.D.
| Room 5065, BSRB, 109 Zina Pitcher Place |
| Ann Arbor, MI 48109 |
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Precise connection and assembly of synapses are critical to process information underlying all neural activity, and thus for proper functioning of the nervous system; abnormal synapse formation causes various neurological and psychiatric disorders. The goal of my laboratory is to reveal the molecular mechanisms of proper neural network and synapse formation in vivo, and to implicate them to treatment of diseases with synaptic malfunction.
During development, synapses are formed by signaling between the presynaptic neuron and its specific postsynaptic target. Target-derived 'presynaptic organizers' promote local differentiation of presynaptic axons into functional nerve terminals at sites of synaptic contact; conversely, the axon directs the target cells to aggregate neurotransmitter receptors and other components of the postsynaptic apparatus (reviewed in Fox and Umemori, J. Neurochem., 2006). We purified such 'presynaptic organizers' using clustering of synaptic vesicles in cultured neurons as an assay, and identified several molecules that can promote presynaptic differentiation as synapses form. Using culture systems and mouse mutants, we are studying the synaptogenic role of those organizers both in vitro and in vivo, especially, their common and distinct functions, and the restricted effects of specific neuronal populations, to reveal the mechanism of specific neural circuit and synapse formation.
One of the organizers we identified was fibroblast growth factor 22 (FGF22). We showed that FGF22 is critical for presynaptic differentiation in the mammalian brain. Inactivating FGF22 or its receptor FGFR2 markedly reduced synapse formation between pontine axons and cerebellar granule cells both in culture and in developing mice, indicating that FGF22 is a crucial presynaptic organizer in the cerebellum (Umemori et al., Cell, 2004). We are currently testing whether various FGFs play multiple roles in the formation and maturation of specific synaptic connections in the brain.
Recently, we identified three presynaptic organizers (FGF7/10/22, laminin beta2 and collagen IV) involved in the neuromuscular junction formation. Using mouse mutants, we found that these target-derived cues act sequentially to organize presynaptic differentiation, with FGF7/10/22, laminin beta2, and collagen IV playing predominant roles in induction, maturation and maintenance of the motor nerve terminal, respectively (Fox et al., Cell, in press). We are investigating whether similar sequential models would explain the presence of multiple organizers at synapses in the brain.
We will continue to identify and analyze synaptic organizers and their downstream mediators critical for specific synapse formation in vivo, using mouse genetics, imaging, biochemistry, histology, molecular and cellular biology, and behavioral analysis. Through our work, we hope to gain insight into the temporal and spatial specificity of proper neural network and synapse formation in the mammalian nervous system, and to lead to treatment and prevention of neurological disorders with abnormal synapse formation.
Fox MA, Sanes JR, Borza DB, Eswarkumar VP, Fassler R, Hudson B, John SWM, Ninomiya Y, Pedchenko V, Pfaff SL, Rheault M, Sado Y, Segal Y, Werle MJ, & Umemori H. Distinct target-derived signals organize formation, maturation and maintenance of motor nerve terminals. Cell, in press.
Fox MA, & Umemori H. Seeking long term relationship: Axon and target communicate to organize synaptic differentiation. J. Neurochem. 97, 1215-1231 (2006).
Umemori H, Linhoff MW, Ornitz DM, & Sanes JR. FGF22 and its close relatives are presynaptic organizing molecules in the mammalian brain. Cell 118, 257-270 (2004). [Cover Article]
Umemori H, Ogura H, Tozawa N, Mikoshiba K, Nishizumi H, & Yamamoto T. Impairment of N-methyl-D-aspartate receptor-controlled motor activity in Lyn-deficient mice. Neuroscience 118, 709-713 (2003).
Yoshida Y, Tanaka S, Umemori H, Minowa O, Usui M, Ikematsu N, Hosoda E, Imamura T, Kuno J, Yamashita T, Miyazono K, Noda M, Noda T, & Yamamoto T. Negative regulation of BMP/Smad signaling by Tob in osteoblasts. Cell 103, 1085-1097 (2000).
Umemori H, Kadowaki Y, Hirosawa K, Yoshida Y, Hironaka K, Okano H, & Yamamoto T. Stimulation of myelin basic protein gene transcription by Fyn tyrosine kinase for myelination. J. Neurosci., 19, 1393-1397 (1999).
Hayashi T, Umemori H, Mishina M, & Yamamoto T. The AMPA receptor interacts with and signals through the protein tyrosine kinase Lyn. Nature 397, 72-76 (1999).
Tezuka T, Umemori H, Akiyama T, Nakanishi S, & Yamamoto T. PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the N-methyl-D-aspartate receptor subunit NR2A. Proc. Natl. Acad. Sci. USA 96, 435-440 (1999).
Umemori H, Inoue T, Kume S, Sekiyama N, Nagao M, Itoh H, Nakanishi S, Mikoshiba K, & Yamamoto T. Activation of the G protein Gq/11 through tyrosine phosphorylation of the alpha subunit. Science 276, 1878-1881, (1997).
Umemori H, Sato S, Yagi T, Aizawa S, & Yamamoto T. Initial events of myelination involve Fyn tyrosine kinase signalling. Nature 367, 572-576 (1994).
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