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    By Alpha|By Interest|Emeritus

Hisashi Umemori, MD
Research Assistant Professor, MBNI
Assistant Professor, Department of Biological Chemistry

5065 BSRB
109 Zina Pitcher Place
Ann Arbor, MI 48109-2200




[ postdoc positions are available ]

Current Research Interests:

Wiring the Functional Nervous System

We study the mechanism of functional neural circuit and synapse formation in the nervous system, using genetically-engineered mice and cultures.

Precise assembly of synapses is critical to process information, 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 mechanism of proper synapse formation, and to implicate them to treatment of diseases with synaptic malfunction.

Identification of “Synaptic Organizers”

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 purified such “presynaptic organizers” using clustering of synaptic vesicles in cultured neurons as an assay, and 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 these organizers both in vitro and in vivo, especially their distinct functions to reveal the mechanism of specific neural circuit and synapse formation.

FGFs as Presynaptic Organizers

One of the organizers we identified is FGF22 (Fibroblast Growth Factor 22). 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 investigating whether multiple FGFs play differential roles in the formation and maturation of specific synaptic connections.

Multiple Presynaptic Organizers Pattern the Synapse

We identified three kinds of presynaptic organizers (FGF7/10/22, laminin beta2 and collagen alpha4) that are involved in the neuromuscular junction (NMJ) formation; they are sequentially involved in the induction, maturation and maintenance of the functional NMJ, respectively (Fox et al., Cell, 2007). We are now focusing on brain synapses. We have identified FGFs and SIRPs (Signal Regulatory Proteins; Umemori and Sanes, JBC, 2008) as presynaptic organizers in the brain. By analyzing the specific role of these molecules in synapse formation, we will understand how multiple organizers cooperate to organize functional synapses in the brain.

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 search for synaptic organizers and their downstream mediators critical for specific neural circuit and synapse formation in vivo, using biochemistry, histology, molecular and cellular biology, mouse genetics, imaging and behavioral analyses. Our work should lead to the treatment and prevention of neurological disorders with abnormal synapse formation.

In mouse embryos lacking FGFR2 (right), synaptic vesicles (green=synaptophysin) remained diffusely distributed in axons (red=neurofilament) instead of concentrating in nerve terminals (Wild Type; left).


Selected References:

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. Weaving the neuronal net with target-derived fibroblast growth factors. Dev. Growth Differ. 51, 263-270 (2009).

Umemori H* & Sanes JR. Signal regulatory proteins (SIRPs) are secreted presynaptic organizing molecules. J Biol Chem. 283, 34053-34061 (2008). [*corresponding author]

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, 179-193 (2007).

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, 257-70 (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, 709-13 (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).



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