Information

Related Research Units

Inflammatory Bowel Disease Treatment and Research Center Research
Neurology Research
F.M. Kirby Neurobiology Center

Research 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.

Research 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

  1. Establishing functionally segregated dopaminergic circuits. Trends Neurosci. 2025 Jan 24. View Abstract
  2. Molecular basis for shifted receptor recognition by an encephalitic arbovirus. bioRxiv. 2025 Jan 02. View Abstract
  3. (Re)building the nervous system: A review of neuron-glia interactions from development to disease. J Neurochem. 2025 Jan; 169(1):e16258. View Abstract
  4. Adolescent alcohol exposure disrupts episodic-like memory by impairing dopamine synapses in the mouse prelimbic cortex. Neuropharmacology. 2025 Mar 01; 265:110255. View Abstract
  5. Correction: Distinct sets of FGF receptors sculpt excitatory and inhibitory synaptogenesis. Development. 2024 Aug 15; 151(16). View Abstract
  6. Shifts in receptors during submergence of an encephalitic arbovirus. Nature. 2024 Aug; 632(8025):614-621. View Abstract
  7. Synaptic BMAL1 phosphorylation controls circadian hippocampal plasticity. Sci Adv. 2023 10 27; 9(43):eadj1010. View Abstract
  8. The projection-specific signals that establish functionally segregated dopaminergic synapses. Cell. 2023 08 31; 186(18):3845-3861.e24. View Abstract
  9. Activity-Dependent Synapse Refinement: From Mechanisms to Molecules. Neuroscientist. 2024 Dec; 30(6):673-689. View Abstract
  10. The molecular signals that regulate activity-dependent synapse refinement in the brain. Curr Opin Neurobiol. 2023 04; 79:102692. View Abstract
  11. CDKL5 sculpts functional callosal connectivity to promote cognitive flexibility. Mol Psychiatry. 2024 Jun; 29(6):1698-1709. View Abstract
  12. ASD/OCD-Linked Protocadherin-10 Regulates Synapse, But Not Axon, Development in the Amygdala and Contributes to Fear- and Anxiety-Related Behaviors. J Neurosci. 2022 05 25; 42(21):4250-4266. View Abstract
  13. In utero intraocular AAV injection for early gene expression in the developing rodent retina. STAR Protoc. 2021 09 17; 2(3):100742. View Abstract
  14. Female-specific synaptic dysfunction and cognitive impairment in a mouse model of PCDH19 disorder. Science. 2021 04 16; 372(6539). View Abstract
  15. An activity-dependent determinant of synapse elimination in the mammalian brain. Neuron. 2021 04 21; 109(8):1333-1349.e6. View Abstract
  16. A splicing isoform of GPR56 mediates microglial synaptic refinement via phosphatidylserine binding. EMBO J. 2020 08 17; 39(16):e104136. View Abstract
  17. 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
  18. 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
  19. CD47 Protects Synapses from Excess Microglia-Mediated Pruning during Development. Neuron. 2018 10 10; 100(1):120-134.e6. View Abstract
  20. 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
  21. 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
  22. A microRNA negative feedback loop downregulates vesicle transport and inhibits fear memory. Elife. 2016 12 21; 5. View Abstract
  23. Activity-dependent proteolytic cleavage of cell adhesion molecules regulates excitatory synaptic development and function. Neurosci Res. 2017 Mar; 116:60-69. View Abstract
  24. Postsynaptic SDC2 induces transsynaptic signaling via FGF22 for bidirectional synaptic formation. Sci Rep. 2016 09 15; 6:33592. View Abstract
  25. 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
  26. 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
  27. 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
  28. Excitability governs neural development in a hippocampal region-specific manner. Development. 2015 Nov 15; 142(22):3879-91. View Abstract
  29. Distinct sets of FGF receptors sculpt excitatory and inhibitory synaptogenesis. Development. 2015 May 15; 142(10):1818-30. View Abstract
  30. FGF22 signaling regulates synapse formation during post-injury remodeling of the spinal cord. EMBO J. 2015 May 05; 34(9):1231-43. View Abstract
  31. 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
  32. 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
  33. The best-laid plans go oft awry: synaptogenic growth factor signaling in neuropsychiatric disease. Front Synaptic Neurosci. 2014; 6:4. View Abstract
  34. Synapse maturation by activity-dependent ectodomain shedding of SIRPa. Nat Neurosci. 2013 Oct; 16(10):1417-25. View Abstract
  35. Suppression of epileptogenesis-associated changes in response to seizures in FGF22-deficient mice. Front Cell Neurosci. 2013; 7:43. View Abstract
  36. 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
  37. 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
  38. Multiple forms of activity-dependent competition refine hippocampal circuits in vivo. Neuron. 2011 Jun 23; 70(6):1128-42. View Abstract
  39. Specific sets of intrinsic and extrinsic factors drive excitatory and inhibitory circuit formation. Neuroscientist. 2012 Jun; 18(3):271-86. View Abstract
  40. Orchestrating the synaptic network by tyrosine phosphorylation signalling. J Biochem. 2011 Jun; 149(6):641-53. View Abstract
  41. NMDAR2B tyrosine phosphorylation regulates anxiety-like behavior and CRF expression in the amygdala. Mol Brain. 2010 Nov 30; 3:37. View Abstract
  42. Secreted factors as synaptic organizers. Eur J Neurosci. 2010 Jul; 32(2):181-90. View Abstract
  43. Distinct FGFs promote differentiation of excitatory and inhibitory synapses. Nature. 2010 Jun 10; 465(7299):783-7. View Abstract
  44. Involvement of NMDAR2A tyrosine phosphorylation in depression-related behaviour. EMBO J. 2009 Dec 02; 28(23):3717-29. View Abstract
  45. Weaving the neuronal net with target-derived fibroblast growth factors. Dev Growth Differ. 2009 Apr; 51(3):263-70. View Abstract
  46. Signal regulatory proteins (SIRPS) are secreted presynaptic organizing molecules. J Biol Chem. 2008 Dec 05; 283(49):34053-61. View Abstract
  47. 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
  48. Distinct target-derived signals organize formation, maturation, and maintenance of motor nerve terminals. Cell. 2007 Apr 06; 129(1):179-93. View Abstract
  49. NR2B tyrosine phosphorylation modulates fear learning as well as amygdaloid synaptic plasticity. EMBO J. 2006 Jun 21; 25(12):2867-77. View Abstract
  50. Seeking long-term relationship: axon and target communicate to organize synaptic differentiation. J Neurochem. 2006 Jun; 97(5):1215-31. View Abstract
  51. 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
  52. FGF22 and its close relatives are presynaptic organizing molecules in the mammalian brain. Cell. 2004 Jul 23; 118(2):257-70. View Abstract
  53. Mice lacking a transcriptional corepressor Tob are predisposed to cancer. Genes Dev. 2003 May 15; 17(10):1201-6. View Abstract
  54. Tob proteins enhance inhibitory Smad-receptor interactions to repress BMP signaling. Mech Dev. 2003 May; 120(5):629-37. View Abstract
  55. 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
  56. 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
  57. Impairment of N-methyl-D-aspartate receptor-controlled motor activity in LYN-deficient mice. Neuroscience. 2003; 118(3):709-13. View Abstract
  58. 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
  59. Negative regulation of BMP/Smad signaling by Tob in osteoblasts. Cell. 2000 Dec 22; 103(7):1085-97. View Abstract
  60. 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
  61. Involvement of protein tyrosine phosphatases in activation of the trimeric G protein Gq/11. Oncogene. 1999 Dec 02; 18(51):7399-402. View Abstract
  62. 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
  63. Distinctive roles of Fyn and Lyn in IgD- and IgM-mediated signaling. Int Immunol. 1999 Sep; 11(9):1441-9. View Abstract
  64. Stimulation of myelin basic protein gene transcription by Fyn tyrosine kinase for myelination. J Neurosci. 1999 Feb 15; 19(4):1393-7. View Abstract
  65. 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
  66. The AMPA receptor interacts with and signals through the protein tyrosine kinase Lyn. Nature. 1999 Jan 07; 397(6714):72-6. View Abstract
  67. Src family tyrosine kinases associate with and phosphorylate CTLA-4 (CD152). Biochem Biophys Res Commun. 1998 Aug 19; 249(2):444-8. View Abstract
  68. 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
  69. Phosphorylation-dependent regulation of N-methyl-D-aspartate receptors by calmodulin. J Biol Chem. 1997 Aug 15; 272(33):20805-10. View Abstract
  70. Activation of the G protein Gq/11 through tyrosine phosphorylation of the alpha subunit. Science. 1997 Jun 20; 276(5320):1878-81. View Abstract
  71. 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
  72. 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
  73. Initial events of myelination involve Fyn tyrosine kinase signalling. Nature. 1994 Feb 10; 367(6463):572-6. View Abstract
  74. 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
  75. 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

Contact Hisashi Umemori

Phone: 617-919-1363
Print Profile