Research

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Hisashi  Umemori, MD, PhD

Hisashi Umemori
Research Center:
F.M. Kirby Neurobiology Center
Program:
Neurobiology Program
Department:
Neurology Research
Hospital Title:
Research Associate
Academic Title:
Associate Professor of Neurology, Harvard Medical School
Research Focus Area:
Wiring the Functional Brain
Contact:
617-919-1363
Contact Via Email
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Research Overview

In the brain, information processing occurs at synapses, and defects in synapse formation underlie many neurological and psychiatric diseases; thus, precise organization of synapses is critical for proper functioning of the brain. We are therefore interested in the molecules and mechanisms by which specific and functional synaptic connections are established in the brain, and are applying our findings to the prevention and treatment of disorders associated with abnormal synapse formation, such as autism, schizophrenia, and epilepsy. We use molecular & cellular biological, mouse genetics, biochemical, histological, physiological, behavioral, and imaging techniques.

Specifically, we identify molecules and mechanisms crucial for synapse formation, focusing on two critical steps during synapse development: 1) differentiation of specific synapses (such as excitatory vs. inhibitory synapses) and 2) activity-dependent refinement of functional synapses (i.e., stabilization of active synapses and elimination of inactive synapses). We establish in vitro and in vivo systems to investigate these steps, analyze the underlying mechanisms, and identify critical determinants for the establishment of appropriate synaptic circuits in the mammalian brain. For example, we have performed an unbiased search (biochemical purification) and identified that FGFs are critical for synaptic differentiation in the mammalian brain (Cell 2004) and showed that three molecules (FGF, laminin, collagen) act sequentially to organize neuromuscular junctions in vivo (Cell 2007). Remarkably, we have identified FGF22 and FGF7 as molecules that promote the organization of excitatory and inhibitory synapses, respectively, in the hippocampus in vivo, and showed that FGF22-deficient mice are resistant to epileptic seizures, and FGF7-deficient mice are prone to them (Nature 2010). Furthermore, we have established a genetic system in which neural activity can be conditionally controlled and demonstrated how functional memory circuits are built in vivo (Neuron 2011). We have also identified signal regulatory proteins (SIRPs) as synaptogenic molecules (JBC 2008) that are involved in the activity-dependent step of synapse maturation (Nature Neuroscience 2013).

Through our work, we aim to understand the principle of mammalian brain wiring and how the functional brain is built. The knowledge obtained will be applied to prevent or treat neurological and psychiatric disorders.

About Hisashi Umemori

Hisashi Umemori’s initial training was as M.D. (University of Tokyo), but early in his clinical career, he decided to devote himself to understanding the basis of the neurological diseases that he was unable to treat properly. At the University of Tokyo, he analyzed the molecular mechanisms underlying myelination (Ph.D. work) and synaptic plasticity. These studies kindled his interest in how synapses form in the brain - As a postdoctoral fellow in Joshua Sanes’ lab at Washington University and Harvard University, Dr. Umemori started studying synapse formation. He joined the faculty of the University of Michigan in 2006 and returned to Harvard University and joined the F.M. Kirby Neurobiology Center at Boston Children's Hospital in 2013, deciphering the cellular and molecular mechanisms underlying the establishment of specific and functional synaptic connections in the brain.

Dr. Umemori received awards from Klingenstein Fellowship, Robert H. Ebert Clinical Scholar, Mallinckrodt Foundation, March of Dimes Foundation, and Whitehall Foundation.

Publications

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  1. Hu HT, Umemori H, Hsueh YP. Postsynaptic SDC2 induces transsynaptic signaling via FGF22 for bidirectional synaptic formation. Sci Rep. 2016 Sep 15; 6:33592.
  2. Terauchi A, Johnson-Venkatesh EM, Bullock B, Lehtinen MK, Umemori H. Retrograde fibroblast growth factor 22 (FGF22) signaling regulates insulin-like growth factor 2 (IGF2) expression for activity-dependent synapse stabilization in the mammalian brain. Elife. 2016 Apr 15; 5.
  3. Dabrowski A, Umemori H. Buttressing a balanced brain: Target-derived FGF signaling regulates excitatory/inhibitory tone and adult neurogenesis within the maturating hippocampal network. Neurogenesis (Austin). 2016; 3(1):e1168504.
  4. Williams AJ, Yee P, Smith MC, Murphy GG, Umemori H. Deletion of fibroblast growth factor 22 (FGF22) causes a depression-like phenotype in adult mice. Behav Brain Res. 2016 Jul 1; 307:11-7.
  5. Dabrowski A, Terauchi A, Strong C, Umemori H. Distinct sets of FGF receptors sculpt excitatory and inhibitory synaptogenesis. Development. 2015 May 15; 142(10):1818-30.
  6. Jacobi A, Loy K, Schmalz AM, Hellsten M, Umemori H, Kerschensteiner M, Bareyre FM. FGF22 signaling regulates synapse formation during post-injury remodeling of the spinal cord. EMBO J. 2015 May 5; 34(9):1231-43.
  7. Wang Q, Terauchi A, Yee CH, Umemori H, Traynor JR. 5-HT1A receptor-mediated phosphorylation of extracellular signal-regulated kinases (ERK1/2) is modulated by regulator of G protein signaling protein 19. Cell Signal. 2014 Sep; 26(9):1846-52.
  8. Williams AJ, Umemori H. The best-laid plans go oft awry: synaptogenic growth factor signaling in neuropsychiatric disease. Front Synaptic Neurosci. 2014; 6:4.
  9. Toth AB, Terauchi A, Zhang LY, Johnson-Venkatesh EM, Larsen DJ, Sutton MA, Umemori H. Synapse maturation by activity-dependent ectodomain shedding of SIRPa. Nat Neurosci. 2013 Oct; 16(10):1417-25.
  10. Lee CH, Umemori H. Suppression of epileptogenesis-associated changes in response to seizures in FGF22-deficient mice. Front Cell Neurosci. 2013; 7:43.
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  12. Lee CH, Javed D, Althaus AL, Parent JM, Umemori H. Neurogenesis is enhanced and mossy fiber sprouting arises in FGF7-deficient mice during development. Mol Cell Neurosci. 2012 Nov; 51(3-4):61-7.
  13. Singh R, Su J, Brooks J, Terauchi A, Umemori H, Fox MA. Fibroblast growth factor 22 contributes to the development of retinal nerve terminals in the dorsal lateral geniculate nucleus. Front Mol Neurosci. 2012; 4:61.
  14. Terauchi A, Umemori H. Specific sets of intrinsic and extrinsic factors drive excitatory and inhibitory circuit formation. Neuroscientist. 2012 Jun; 18(3):271-86.
  15. Dabrowski A, Umemori H. Orchestrating the synaptic network by tyrosine phosphorylation signalling. J Biochem. 2011 Jun; 149(6):641-53.
  16. Delawary M, Tezuka T, Kiyama Y, Yokoyama K, Inoue T, Hattori S, Hashimoto R, Umemori H, Manabe T, Yamamoto T, Nakazawa T. NMDAR2B tyrosine phosphorylation regulates anxiety-like behavior and CRF expression in the amygdala. Mol Brain. 2010 Nov 30; 3:37.
  17. Johnson-Venkatesh EM, Umemori H. Secreted factors as synaptic organizers. Eur J Neurosci. 2010 Jul; 32(2):181-90.
  18. Terauchi A, Johnson-Venkatesh EM, Toth AB, Javed D, Sutton MA, Umemori H. Distinct FGFs promote differentiation of excitatory and inhibitory synapses. Nature. 2010 Jun 10; 465(7299):783-7.
  19. Taniguchi S, Nakazawa T, Tanimura A, Kiyama Y, Tezuka T, Watabe AM, Katayama N, Yokoyama K, Inoue T, Izumi-Nakaseko H, Kakuta S, Sudo K, Iwakura Y, Umemori H, Inoue T, Murphy NP, Hashimoto K, Kano M, Manabe T, Yamamoto T. Involvement of NMDAR2A tyrosine phosphorylation in depression-related behaviour. EMBO J. 2009 Dec 2; 28(23):3717-29.
  20. Umemori H. Weaving the neuronal net with target-derived fibroblast growth factors. Dev Growth Differ. 2009 Apr; 51(3):263-70.
  21. Umemori H, Sanes JR. Signal regulatory proteins (SIRPS) are secreted presynaptic organizing molecules. J Biol Chem. 2008 Dec 5; 283(49):34053-61.
  22. Nakazawa T, Kuriu T, Tezuka T, Umemori H, Okabe S, Yamamoto T. Regulation of dendritic spine morphology by an NMDA receptor-associated Rho GTPase-activating protein, p250GAP. J Neurochem. 2008 May; 105(4):1384-93.
  23. Fox MA, Sanes JR, Borza DB, Eswarakumar VP, Fässler R, Hudson BG, John SW, Ninomiya Y, Pedchenko V, Pfaff SL, Rheault MN, Sado Y, Segal Y, Werle MJ, Umemori H. Distinct target-derived signals organize formation, maturation, and maintenance of motor nerve terminals. Cell. 2007 Apr 6; 129(1):179-93.
  24. Nakazawa T, Komai S, Watabe AM, Kiyama Y, Fukaya M, Arima-Yoshida F, Horai R, Sudo K, Ebine K, Delawary M, Goto J, Umemori H, Tezuka T, Iwakura Y, Watanabe M, Yamamoto T, Manabe T. NR2B tyrosine phosphorylation modulates fear learning as well as amygdaloid synaptic plasticity. EMBO J. 2006 Jun 21; 25(12):2867-77.
  25. Fox MA, Umemori H. Seeking long-term relationship: axon and target communicate to organize synaptic differentiation. J Neurochem. 2006 Jun; 97(5):1215-31.
  26. Umemori H, Linhoff MW, Ornitz DM, Sanes JR. FGF22 and its close relatives are presynaptic organizing molecules in the mammalian brain. Cell. 2004 Jul 23; 118(2):257-70.
  27. Yoshida Y, Nakamura T, Komoda M, Satoh H, Suzuki T, Tsuzuku JK, Miyasaka T, Yoshida EH, Umemori H, Kunisaki RK, Tani K, Ishii S, Mori S, Suganuma M, Noda T, Yamamoto T. Mice lacking a transcriptional corepressor Tob are predisposed to cancer. Genes Dev. 2003 May 15; 17(10):1201-6.
  28. Yoshida Y, von Bubnoff A, Ikematsu N, Blitz IL, Tsuzuku JK, Yoshida EH, Umemori H, Miyazono K, Yamamoto T, Cho KW. Tob proteins enhance inhibitory Smad-receptor interactions to repress BMP signaling. Mech Dev. 2003 May; 120(5):629-37.
  29. Nakazawa T, Watabe AM, Tezuka T, Yoshida Y, Yokoyama K, Umemori H, Inoue A, Okabe S, Manabe T, Yamamoto T. p250GAP, a novel brain-enriched GTPase-activating protein for Rho family GTPases, is involved in the N-methyl-d-aspartate receptor signaling. Mol Biol Cell. 2003 Jul; 14(7):2921-34.
  30. Kohda K, Kamiya Y, Matsuda S, Kato K, Umemori H, Yuzaki M. Heteromer formation of delta2 glutamate receptors with AMPA or kainate receptors. Brain Res Mol Brain Res. 2003 Jan 31; 110(1):27-37.
  31. 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. 2003; 118(3):709-13.
  32. Nakazawa T, Komai S, Tezuka T, Hisatsune C, Umemori H, Semba K, Mishina M, Manabe T, Yamamoto T. Characterization of Fyn-mediated tyrosine phosphorylation sites on GluR epsilon 2 (NR2B) subunit of the N-methyl-D-aspartate receptor. J Biol Chem. 2001 Jan 5; 276(1):693-9.
  33. 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. 2000 Dec 22; 103(7):1085-97.
  34. Hironaka K, Umemori H, Tezuka T, Mishina M, Yamamoto T. The protein-tyrosine phosphatase PTPMEG interacts with glutamate receptor delta 2 and epsilon subunits. J Biol Chem. 2000 May 26; 275(21):16167-73.
  35. 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. 1999 Dec 2; 18(51):7399-402.
  36. Hisatsune C, Umemori H, Mishina M, Yamamoto T. Phosphorylation-dependent interaction of the N-methyl-D-aspartate receptor epsilon 2 subunit with phosphatidylinositol 3-kinase. Genes Cells. 1999 Nov; 4(11):657-66.
  37. Horikawa K, Nishizumi H, Umemori H, Aizawa S, Takatsu K, Yamamoto T. Distinctive roles of Fyn and Lyn in IgD- and IgM-mediated signaling. Int Immunol. 1999 Sep; 11(9):1441-9.
  38. 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. 1999 Feb 15; 19(4):1393-7.
  39. Hayashi T, Umemori H, Mishina M, Yamamoto T. The AMPA receptor interacts with and signals through the protein tyrosine kinase Lyn. Nature. 1999 Jan 7; 397(6714):72-6.
  40. Miyatake S, Nakaseko C, Umemori H, Yamamoto T, Saito T. Src family tyrosine kinases associate with and phosphorylate CTLA-4 (CD152). Biochem Biophys Res Commun. 1998 Aug 19; 249(2):444-8.
  41. Yoshida Y, Matsuda S, Ikematsu N, Kawamura-Tsuzuku J, Inazawa J, Umemori H, Yamamoto T. ANA, a novel member of Tob/BTG1 family, is expressed in the ventricular zone of the developing central nervous system. Oncogene. 1998 May; 16(20):2687-93.
  42. Hisatsune C, Umemori H, Inoue T, Michikawa T, Kohda K, Mikoshiba K, Yamamoto T. Phosphorylation-dependent regulation of N-methyl-D-aspartate receptors by calmodulin. J Biol Chem. 1997 Aug 15; 272(33):20805-10.
  43. 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. 1997 Jun 20; 276(5320):1878-81.
  44. Fusaki N, Matsuda S, Nishizumi H, Umemori H, Yamamoto T. Physical and functional interactions of protein tyrosine kinases, p59fyn and ZAP-70, in T cell signaling. J Immunol. 1996 Feb 15; 156(4):1369-77.
  45. Umemori H, Sato S, Yagi T, Aizawa S, Yamamoto T. Initial events of myelination involve Fyn tyrosine kinase signalling. Nature. 1994 Feb 10; 367(6463):572-6.
  46. Yamanashi Y, Okada M, Semba T, Yamori T, Umemori H, Tsunasawa S, Toyoshima K, Kitamura D, Watanabe T, Yamamoto T. Identification of HS1 protein as a major substrate of protein-tyrosine kinase(s) upon B-cell antigen receptor-mediated signaling. Proc Natl Acad Sci U S A. 1993 Apr 15; 90(8):3631-5.
  47. Umemori H, Wanaka A, Kato H, Takeuchi M, Tohyama M, Yamamoto T. Specific expressions of Fyn and Lyn, lymphocyte antigen receptor-associated tyrosine kinases, in the central nervous system. Brain Res Mol Brain Res. 1992 Dec; 16(3-4):303-10.
  48. Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem. 2006 Jun 9; 281(23):15694-700.
  49. 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 U S A. 1999 Jan 19; 96(2):435-40.
  50. Tezuka T, Umemori H, Fusaki N, Yagi T, Takata M, Kurosaki T, Yamamoto T. Physical and functional association of the cbl protooncogen product with an src-family protein tyrosine kinase, p53/56lyn, in the B cell antigen receptor-mediated signaling. J Exp Med. 1996 Feb 1; 183(2):675-80.
  51. 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. 2011 Jun 23; 70(6):1128-42.
  52. Terauchi A, Timmons KM, Kikuma K, Pechmann Y, Kneussel M, Umemori H. Selective synaptic targeting of the excitatory and inhibitory presynaptic organizers FGF22 and FGF7. J Cell Sci. 2015 Jan 15; 128(2):281-92.
  53. Johnson-Venkatesh EM, Khan MN, Murphy GG, Sutton MA, Umemori H. Excitability governs neural development in a hippocampal region-specific manner. Development. 2015 Nov 15; 142(22):3879-91.
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F.M. Kirby Neurobiology Center

The F.M. Kirby Neurobiology Center, together with the Neurobiology Program at Boston Children’s Hospital, is the largest basic neuroscience research enterprise at a U.S. hospital. It incorporates basic and translational neuroscience research, focusing primarily on developmental neurobiology.

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