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

MBNI Labs at Medical Science Research Building II C560E
1150 W. Medical Center Drive
Ann Arbor, MI 48109-0669

umemoh@umich.edu

734-763-5242

Current Research Interests:

Neural Circuit and Synapse Formation

We study the neural circuit and synapse formation in the nervous system using genetically-engineered mice.

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”

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 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, FGF22 was shown to be 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. We are currently testing whether various FGFs play multiple roles in the formation and maturation of synaptic connections.

Multiple Presynaptic Organizers Pattern the Synapse

Recently, we identified three kinds of presynaptic organizers (FGF7/10/22, laminin b2 and collagen a (IV)) involved in the neuromuscular junction formation, and found that they are sequentially working to induce, maturate and maintain the nerve terminal, respectively. Similar sequential models might help explain the presence of multiple organizers at synapses in the brain.

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.

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

Selected References:

Fox MA, Umemori H.
Seeking long term relationship: Axon and target communicate to organize synaptic differentiation.
J. Neurochem. in press (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).