ABOUT THE RESEARCHER

OVERVIEW

Information processing in the brain occurs at synapses. Defects in synapse development underlie many neurological and psychiatric diseases. We are therefore interested in the molecules and manner by which specific and functional synaptic circuits are established in the mammalian brain. We then apply our findings to the prevention and treatment of disorders associated with abnormal synapse development, such as autism, schizophrenia, and epilepsy.

Specifically, we identify molecules and mechanisms that regulate:

  1. Development of specific synaptic circuits. In the brain, there are many distinct circuits that regulate a variety of behaviors. We investigate how specific synaptic circuits are established and function to regulate specific behaviors.
  2. Activity-dependent refinement of synaptic circuits. To establish the most efficient synaptic circuits, synaptic connections must be refined by neural activity during the final stage of synapse development. We investigate how functional synaptic circuits are established in the brain in vivo.

We use molecular and cellular, mouse genetic, imaging, physiological, behavioral, and optogenetic techniques. 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. For more information, please go to umemorilab.org.

BACKGROUND

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 neuropsychiatric 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 development. 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 Children's Hospital in 2013, deciphering the mechanisms underlying the establishment and function of specific and functional synaptic circuits in the mammalian 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. Female-specific synaptic dysfunction and cognitive impairment in a mouse model of PCDH19 disorder. Science. 2021 04 16; 372(6539). View abstract
  2. An activity-dependent determinant of synapse elimination in the mammalian brain. Neuron. 2021 04 21; 109(8):1333-1349.e6. View abstract
  3. A splicing isoform of GPR56 mediates microglial synaptic refinement via phosphatidylserine binding. EMBO J. 2020 08 17; 39(16):e104136. View abstract
  4. Optimizing Nervous System-Specific Gene Targeting with Cre Driver Lines: Prevalence of Germline Recombination and Influencing Factors. Neuron. 2020 04 08; 106(1):37-65.e5. View abstract
  5. Neuronal fibroblast growth factor 22 signaling during development, but not in adults, is involved in anhedonia. Neuroreport. 2020 01 27; 31(2):125-130. View abstract
  6. CD47 Protects Synapses from Excess Microglia-Mediated Pruning during Development. Neuron. 2018 10 10; 100(1):120-134.e6. View abstract
  7. Tyrosine phosphorylation of the transmembrane protein SIRPa: Sensing synaptic activity and regulating ectodomain cleavage for synapse maturation. J Biol Chem. 2018 08 03; 293(31):12026-12042. View abstract
  8. Selective Inactivation of Fibroblast Growth Factor 22 (FGF22) in CA3 Pyramidal Neurons Impairs Local Synaptogenesis and Affective Behavior Without Affecting Dentate Neurogenesis. Front Synaptic Neurosci. 2017; 9:17. View abstract
  9. A microRNA negative feedback loop downregulates vesicle transport and inhibits fear memory. Elife. 2016 12 21; 5. View abstract
  10. Activity-dependent proteolytic cleavage of cell adhesion molecules regulates excitatory synaptic development and function. Neurosci Res. 2017 Mar; 116:60-69. View abstract
  11. Postsynaptic SDC2 induces transsynaptic signaling via FGF22 for bidirectional synaptic formation. Sci Rep. 2016 09 15; 6:33592. View abstract
  12. 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 04 15; 5. View abstract
  13. 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. View abstract
  14. Deletion of fibroblast growth factor 22 (FGF22) causes a depression-like phenotype in adult mice. Behav Brain Res. 2016 07 01; 307:11-7. View abstract
  15. Excitability governs neural development in a hippocampal region-specific manner. Development. 2015 Nov 15; 142(22):3879-91. View abstract
  16. Distinct sets of FGF receptors sculpt excitatory and inhibitory synaptogenesis. Development. 2015 May 15; 142(10):1818-30. View abstract
  17. FGF22 signaling regulates synapse formation during post-injury remodeling of the spinal cord. EMBO J. 2015 May 05; 34(9):1231-43. View abstract
  18. Selective synaptic targeting of the excitatory and inhibitory presynaptic organizers FGF22 and FGF7. J Cell Sci. 2015 Jan 15; 128(2):281-92. View abstract
  19. 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. View abstract
  20. The best-laid plans go oft awry: synaptogenic growth factor signaling in neuropsychiatric disease. Front Synaptic Neurosci. 2014; 6:4. View abstract
  21. Synapse maturation by activity-dependent ectodomain shedding of SIRPa. Nat Neurosci. 2013 Oct; 16(10):1417-25. View abstract
  22. Suppression of epileptogenesis-associated changes in response to seizures in FGF22-deficient mice. Front Cell Neurosci. 2013; 7:43. View abstract
  23. Neurogenesis is enhanced and mossy fiber sprouting arises in FGF7-deficient mice during development. Mol Cell Neurosci. 2012 Nov; 51(3-4):61-7. View abstract
  24. Fibroblast growth factor 22 contributes to the development of retinal nerve terminals in the dorsal lateral geniculate nucleus. Front Mol Neurosci. 2012; 4:61. View abstract
  25. Multiple forms of activity-dependent competition refine hippocampal circuits in vivo. Neuron. 2011 Jun 23; 70(6):1128-42. View abstract
  26. Specific sets of intrinsic and extrinsic factors drive excitatory and inhibitory circuit formation. Neuroscientist. 2012 Jun; 18(3):271-86. View abstract
  27. Orchestrating the synaptic network by tyrosine phosphorylation signalling. J Biochem. 2011 Jun; 149(6):641-53. View abstract
  28. NMDAR2B tyrosine phosphorylation regulates anxiety-like behavior and CRF expression in the amygdala. Mol Brain. 2010 Nov 30; 3:37. View abstract
  29. Secreted factors as synaptic organizers. Eur J Neurosci. 2010 Jul; 32(2):181-90. View abstract
  30. Distinct FGFs promote differentiation of excitatory and inhibitory synapses. Nature. 2010 Jun 10; 465(7299):783-7. View abstract
  31. Involvement of NMDAR2A tyrosine phosphorylation in depression-related behaviour. EMBO J. 2009 Dec 02; 28(23):3717-29. View abstract
  32. Weaving the neuronal net with target-derived fibroblast growth factors. Dev Growth Differ. 2009 Apr; 51(3):263-70. View abstract
  33. Signal regulatory proteins (SIRPS) are secreted presynaptic organizing molecules. J Biol Chem. 2008 Dec 05; 283(49):34053-61. View abstract
  34. Regulation of dendritic spine morphology by an NMDA receptor-associated Rho GTPase-activating protein, p250GAP. J Neurochem. 2008 May; 105(4):1384-93. View abstract
  35. Distinct target-derived signals organize formation, maturation, and maintenance of motor nerve terminals. Cell. 2007 Apr 06; 129(1):179-93. View abstract
  36. NR2B tyrosine phosphorylation modulates fear learning as well as amygdaloid synaptic plasticity. EMBO J. 2006 Jun 21; 25(12):2867-77. View abstract
  37. Seeking long-term relationship: axon and target communicate to organize synaptic differentiation. J Neurochem. 2006 Jun; 97(5):1215-31. View abstract
  38. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem. 2006 Jun 09; 281(23):15694-700. View abstract
  39. FGF22 and its close relatives are presynaptic organizing molecules in the mammalian brain. Cell. 2004 Jul 23; 118(2):257-70. View abstract
  40. Mice lacking a transcriptional corepressor Tob are predisposed to cancer. Genes Dev. 2003 May 15; 17(10):1201-6. View abstract
  41. Tob proteins enhance inhibitory Smad-receptor interactions to repress BMP signaling. Mech Dev. 2003 May; 120(5):629-37. View abstract
  42. 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. View abstract
  43. Heteromer formation of delta2 glutamate receptors with AMPA or kainate receptors. Brain Res Mol Brain Res. 2003 Jan 31; 110(1):27-37. View abstract
  44. Impairment of N-methyl-D-aspartate receptor-controlled motor activity in LYN-deficient mice. Neuroscience. 2003; 118(3):709-13. View abstract
  45. 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 05; 276(1):693-9. View abstract
  46. Negative regulation of BMP/Smad signaling by Tob in osteoblasts. Cell. 2000 Dec 22; 103(7):1085-97. View abstract
  47. The protein-tyrosine phosphatase PTPMEG interacts with glutamate receptor delta 2 and epsilon subunits. J Biol Chem. 2000 May 26; 275(21):16167-73. View abstract
  48. Involvement of protein tyrosine phosphatases in activation of the trimeric G protein Gq/11. Oncogene. 1999 Dec 02; 18(51):7399-402. View abstract
  49. 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. View abstract
  50. Distinctive roles of Fyn and Lyn in IgD- and IgM-mediated signaling. Int Immunol. 1999 Sep; 11(9):1441-9. View abstract
  51. Stimulation of myelin basic protein gene transcription by Fyn tyrosine kinase for myelination. J Neurosci. 1999 Feb 15; 19(4):1393-7. View abstract
  52. 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. View abstract
  53. The AMPA receptor interacts with and signals through the protein tyrosine kinase Lyn. Nature. 1999 Jan 07; 397(6714):72-6. View abstract
  54. Src family tyrosine kinases associate with and phosphorylate CTLA-4 (CD152). Biochem Biophys Res Commun. 1998 Aug 19; 249(2):444-8. View abstract
  55. 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. View abstract
  56. Phosphorylation-dependent regulation of N-methyl-D-aspartate receptors by calmodulin. J Biol Chem. 1997 Aug 15; 272(33):20805-10. View abstract
  57. Activation of the G protein Gq/11 through tyrosine phosphorylation of the alpha subunit. Science. 1997 Jun 20; 276(5320):1878-81. View abstract
  58. 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. View abstract
  59. 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 01; 183(2):675-80. View abstract
  60. Initial events of myelination involve Fyn tyrosine kinase signalling. Nature. 1994 Feb 10; 367(6463):572-6. View abstract
  61. 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. View abstract
  62. 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. View abstract