Nakanishi Lab

Principal Investigator: Nobuki Nakanishi, PhD  

email: nnakanishi at scintillon dot org

Research Focus: Molecular, cellular and developmental biology

The Nakanishi lab has contributed to the identification of NR3A (GRIN3) subunits of the NMDA receptor family and their physiological and pathophysiological activities.

We have discovered the takusan gene family, which positively regulates synaptic structures and thereby protect synapses from pathological insults.

Specifically, we have generated various GRIN3 mouse mutants (knockout and overexpressor) and studied their phenotypes.

Nakanishi Lab: In-depth

Identification of GRIN3 as a component of the NMDA receptor complex. Through previous work at Harvard Medical School, we identified GRIN3 as a novel subunit of NMDA-type glutamate receptors. At the time of this finding, GRIN1 and GRIN2 had been identified as NMDA receptor subuits. We showed that GRIN3 forms biochemical complex with GRIN1 and GRIN2. We then genetically knocked out GRIN3 gene in mice to show that GRIN3 modifies NMDA-evoked currents and regulates dendritic spine morphology in vivo.

Identification of GRIN3 as a neuroprotective protein in a mouse model of stroke.  While working previously at Sanford Burnham Prebys Medical Discovery Institute, we led the study in which we constructed transgenic mice overexpressing GRIN3 in the brain, not clearly understood at the time, and studied its effects. We have shown that GRIN3 overexpression leads to the reduction in the size of stroke and thus identified GRIN3 as a neuroprotective protein.

Identification of takusan proteins in the mouse brain.  Briefly, we originally identified takusan as a differentially expressed gene in GRIN3 knock out mice.  We then discovered that the mouse genome carries ~200 homoologous genes encoding variants of takusan.  Overexpression of takusan proteins in cultured neurons leads to the modification of dendritic spines.  Importantly, we showed that engineered takusan proteins can protect synapses from Aβ induced damages.

The identification of the transcription factor MEF2 (myocyte enhancer factor-2) as a critical molecule in neuronal development. In addition, we have discovered a novel etiology of Intellectual and Developmental Disabilities (IDD) and Autism-Spectrum Disorders (ASD) based on genetic alterations in one of MEF2 subtypes, MEF2C. In collaboration with the Lipton Lab, we recently generated a conditional brain knockout of Mef2c in mice, which resulted in a decrease in neurogenesis, fewer synapses, and an IDD- and ASD-related phenotype in behavioral tests (published in PNAS). Subsequently, six other laboratories reported that microdeletion of one copy of chromosome regions containing MEF2C in humans resulted in IDD, ASD, and other neurological disorders, making our findings in mice clinically relevant.

Nakanishi Lab Grants

NIH/DHHS P01 “Genetic Approach to Excitatory Transmission”

California Institute of Regenerative Medicine (CIRM) “Programming Human ESC-derived Neural Stem Cells with MEF2C for Transplantation in Stroke”

Selected Publications

  • Nakanishi N, Shneider NA, Axel R (1990) A family of glutamate receptor genes: evidence for the formation of heteromultimeric receptors with distinct channel properties. Neuron 5:569-581. PMCID: PMC4481242
  • Nakanishi N, Axel R, Shneider NA (1992) Alternative splicing generates functionally distinct N-methyl-D-aspartate receptors. Proc Natl Acad Sci USA 89:8552-8556. PMCID: PMC49958
  • Das S, Sasaki YF, Rothe T, Premkumar LS, Takasu M, Crandall JE, Dikkes P, Conner DA, Rayudu PV, Cheung W, Chen HS, Lipton SA, Nakanishi N (1998) Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A. Nature 393:377-381.
  • Sasaki YF, Rothe T, Premkumar LS, Das S, Cui J, Talantova MV, Wong HK, Gong X, Chan SF, Zhang D, Nakanishi N, Sucher NJ, Lipton SA (2002) Characterization and comparison of the NR3A subunit of the NMDA receptor in recombinant systems and primary cortical neurons. J Neurophys 87:2052-2063.
  • Chatterton JE, Awobuluyi M, Premkumar LS, Takahashi H, Talantova M, Shin Y, Cui J, Tu S, Sevarino KA, Nakanishi N, Tong G, Lipton SA, Zhang D (2002) Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature 415:793-798.
  • Tong G, Takahashi H, Tu S, Shin Y, Talantova M, Zago W, Xia P, Nie Z, Goetz T, Zhang D, Lipton SA, Nakanishi N (2008) Modulation of NMDA receptor properties and synaptic transmission by the NR3A subunit in mouse hippocampal and cerebrocortical neurons. J Neurophys 99:122-132.
  • Nakanishi N, Tu S, Shin Y, Cui J, Kurokawa T, Zhang D, Chen HS, Tong G, Lipton SA (2009) Neuroprotection by the NR3A subunit of the NMDA receptor. J Neurosci 29:5260-5265. PMCID: PMC2703294
  • Pina-Crespo JC, Talantova M, Micu I, States B, Chen HS, Tu S, Nakanishi N, Tong G, Zhang D, Heinemann SF, Zamponi GW, Stys PK, Lipton SA (2010) Excitatory glycine responses of CNS myelin mediated by NR1/NR3 "NMDA" receptor subunits. The Journal of Neuroscience : J Neurosci 30:11501-11505. PMCID: PMC2941801
  • Larsen RS, Corlew RJ, Henson MA, Roberts AC, Mishina M, Watanabe M, Lipton SA, Nakanishi N, Perez-Otano I, Weinberg RJ, Philpot BD (2011) NR3A-containing NMDARs promote neurotransmitter release and spike timing-dependent plasticity. Nat Neurosci 14:338-344. PMCID: PMC3474337
  • Nakanishi N, Kang Y-J, Tu S, McKercher SR, Masliah E, Lipton SA (2015) Differential effects of pharmacologic and genetic modulation of NMDA receptor activity on HIV/gp120-induced neuronal damage in an in vivo mouse model. J Mol Neurosci (in press)
  • Tu S, Shin Y, Zago WM, States BA, Eroshkin A, Lipton SA, Tong GG, Nakanishi N (2007) Takusan: a large gene family that regulates synaptic activity. Neuron 55:69-85. PMCID: PMC2902460
  • Nakanishi N, Ryan SD, Zhang X, Khan A, Holland T, Cho EG, Huang X, Liao FF, Xu H, Lipton SA, Tu S (2013) Synaptic protein alpha1-takusan mitigates amyloid-beta-induced synaptic loss via interaction with tau and postsynaptic density-95 at postsynaptic sites. J Neurosci 33:14170-14183. PMCID: PMC3756761
  • Li H, Radford JC, Ragusa MJ, Shea KL, McKercher SR, Zaremba JD, Soussou W, Nie Z, Kang YJ, Nakanishi N, Okamoto S, Roberts AJ, Schwarz JJ, Lipton SA (2008) Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo. Proc Natl Acad Sci USA 105:9397-9402. PMCID: PMC2453715
  • Cho EG, Zaremba JD, McKercher SR, Talantova M, Tu S, Masliah E, Chan SF, Nakanishi N, Terskikh A, Lipton SA (2011) MEF2C enhances dopaminergic neuron differentiation of human embryonic stem cells in a parkinsonian rat model. PLOS One 6:e24027. PMCID: PMC3162026
  • Chan SF, Sances S, Brill LM, Okamoto S, Zaidi R, McKercher SR, Akhtar MW, Nakanishi N, Lipton SA (2014) ATM-dependent phosphorylation of MEF2D promotes neuronal survival after DNA damage. J Neurosci 34:4640-4653. PMCID: PMC3965787
  • Chan SF, Huang X, McKercher SR, Zaidi R, Okamoto SI, Nakanishi N, Lipton SA (2015) Transcriptional profiling of MEF2-regulated genes in human neural progenitor cells derived from embryonic stem cells. Genomics Data 3:24-27. PMCID: PMC4255278

Complete List of Published Work in MyBibliography: