Assistant Professor, Biological Chemistry
M.D., Ph.D, University of Tokyo, Faculty of Medicine
Postdoctoral, Washington University School of Medicine
Postdoctoral, Harvard University
Neurons analyze and transmit information in the brain. Information is transferred from one neuron to another at functional contact sites called synapses. Precise assembly of synapses is 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 connection and synapse formation in vivo, and to implicate them to treatment of diseases with synaptic malfunction.
Identification of “Synaptic Organizers”
During development, synapses are formed by signaling between the presynaptic neuron and its specific postsynaptic target. Target-derived “presynaptic organizers” promote local differentiation of 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. We biochemically purified such “presynaptic organizers” using clustering of synaptic vesicles in cultured neurons as an assay, and proteomically identified several molecules that can promote differentiation of nerve terminals as synapses form. Using culture systems and mouse mutants, we study 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.
FGFs as Presynaptic Organizers
One of the organizers we identified is 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). Furthermore, we have recently found that FGF22 and its close relative FGF7 promote the organization of excitatory and inhibitory presynaptic terminals, respectively, as target-derived presynaptic organizers. The differentiation of excitatory or inhibitory nerve terminals in the hippocampus is specifically impaired in mutants lacking FGF22 or FGF7. As expected from the alterations in excitatory/inhibitory balance, FGF22KO mice are resistant and FGF7KO mice are prone to epileptic seizures, indicating that the impairment of presynaptic differentiation has a life-long impact on brain function (Terauchi et al., Nature, 2010). We are currently determining the mechanisms by which FGF22 and FGF7 show differential effects on excitatory and inhibitory presynaptic differentiation, the signaling pathway of FGF-mediated presynaptic differentiation, the functional consequences of FGF-deficiency during development in vivo, the mechanisms by which the impairment of presynaptic differentiation in FGFKO mice leads to formation of epileptic circuits, and FGF's involvement in other neurodevelopmental disorders.
Multiple Presynaptic Organizers Pattern the Synapse
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, 2007). We are now investigating why there are multiple organizers in the brain - whether they are for different synapses, different structures, or different steps - to organize our brain circuitry.
Activity-Dependent Synapse Refinement in vivo
To establish appropriate neural circuits, synaptic connections are further refined by neural activity during development, and are continuously modified to adapt changes in the environment. We are also studying the mechanism underlying this activity-dependent synapse refinement step in the brain in vivo using transgenic mouse systems.
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.
Figure: In mouse embryos lacking FGFR2, synaptic vesicles (green=synaptophysin) remained diffusely distributed in axons (red=neurofilament) instead of concentrating in nerve terminals (Wild Type), indicating that the FGF signaling is critical for recruiting synaptic vesicles to the synaptic terminal.
1993 Inoue Foundation Research Award
1996 The University of Tokyo Research Award
1998 Uehara Memorial Research Fellowship Award
2004 O'Leary Prize (Washington University)
2005 Biological Sciences Scholar (University of Michigan)
2006 Klingenstein Fellowship Award in the Neuroscience
2006 The 8th Robert H. Ebert Clinical Scholar
2006 Edward Mallinckrodt, Jr. Foundation Award
2009 Basil O'Connor Award
2009 Whitehall Foundation Award
Yasuda M, Johnson-Venkatesh EM, Zhang H, Parent JM, Sutton MA, Umemori H.
Multiple forms of activity-dependent competition refine hippocampal circuits in vivo. Neuron in press (2011).
Terauchi A, Johnson-Venkatesh EM, Toth AB, Javed D, Sutton MA, Umemori H.
Distinct FGFs promote differentiation of excitatory and inhibitory synapses. Nature 465, 783-787 (2010).
Johnson-Venkatesh EM, Umemori H.
Secreted factors as synaptic organizers. Eur. J. Neurosci. 32, 181-190 (2010).
Umemori H*, Sanes JR.
Signal regulatory proteins (SIRPs) are secreted presynaptic organizing molecules. J. Biol. Chem. 283, 34053-61 (2008). http://www.jbc.org/cgi/content/full/283/49/34053
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 129, 179-93 (2007). http://www.cell.com/fulltext/S0092-8674(07)00302-9
Fox MA, Umemori H.
Seeking long term relationship: Axon and target communicate to organize synaptic differentiation. J. Neurochem. 97, 1215-31 (2006). http://www3.interscience.wiley.com/cgi-bin/fulltext/118560592/HTMLSTART
Umemori H, Linhoff MW, Ornitz DM, Sanes JR. FGF22 and its close relatives are presynaptic organizing molecules in the mammalian brain. Cell 118, 257-70 (2004). [Cover Article] http://www.cell.com/fulltext/S0092-8674(04)00625-7
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, 709-13 (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, Hayashi T, Inoue T, Nakanishi S, Mikoshiba K, & Yamamoto T.
Involvement of protein tyrosine phosphatases in activation of the trimeric G protein Gq/11. Oncogene 18, 7399-7402 (1999).
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 a 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).