Kazuhito Toyooka, PhD

Associate Professor

Department: Neurobiology & Anatomy

Education

PhD in Immunology - Osaka University, Japan
Shizuoka University, Japan

Other Languages Spoken

Japanese

Dr. Toyooka is an associate professor in the Department of Neurobiology & Anatomy at Drexel University College of Medicine.

Research Interests

Translational research of autism spectrum disorder (ASD), epilepsy and Parkinson’s disease (PD) - Peptide therapy, CRISPR gene therapy, mouse models, patient-derived hiPSCs, gene functions in axon/dendrite outgrowth, spine/synapse formation, neural circuit/activity, and neurobehaviors including sociability, repetitive behavior, learning and memory

Research

Visit Toyooka Lab Website

Ongoing Projects

A translational study evaluating peptide therapy and CRISPR gene therapy as treatments for autism spectrum disorder (ASD).
17p13.3 microdeletion (Miller-Dieker syndrome) and microduplication syndrome – Gene functions in the chromosome 17p13.3 region.
14-3-3 syndromes - Understanding the etiology of neurological diseases associated with 14-3-3 gene mutations: Miller-Dieker syndrome, schizophrenia, neurodegenerative diseases, epilepsy.
Parkinson’s disease (PD) – Novel medication with 14-3-3 modifiers and interaction between α-Synuclein-14-3-3.

We are developing treatments for brain diseases, such as autism spectrum disorder (ASD) and Parkinson's disease (PD). We use three strategies to accomplish this goal: 1) Peptide therapy, 2) Gene therapy using CRISPR, and 3) 14-3-3 modifiers, in both mouse models and human iPSCs derived from patients.

1) A new medication for the treatment of autism spectrum disorder (ASD) as well as an understanding of the neurobiology of ASD.

Using mouse models of ASD and hiPSCs derived from patients with ASD, we investigate the peptides as a potential therapeutic to treat ASD. Additionally, we have developed gene therapy for ASD using CRISPR technology. Additionally, we are investigating the etiology of ASD, focusing on the neurobiology of the gene ADNP (Activity-Dependent Neuroprotective Protein), its role in axon/dendrite growth, spine/synapse formation, neuronal circuits and activity, and neurobehavior, including social interactions, repetitive behaviors, and learning and memory.

2) Understanding of the etiology of the 17p13.3 microdeletion and duplication syndrome.

We are currently investigating the etiology of neurodevelopmental disorders, including 17p13.3 deletion disorder (Miller-Dieker syndrome) associated with lissencephaly and 17p13.3 microduplication syndrome associated with autism.

3) Understanding of the etiology of epilepsy and cognition disorders caused by 14-3-3 gene mutations.

14-3-3 is a multifunctional protein that binds to more than 200 targets and acts as a scaffold protein. A mutation in the 14-3-3 gene, such as the YWHAG coding for the 14-3-3gamma protein, is associated with severe epilepsy. Also, a mutation or deletion of the YWHAE gene, which codes for the 14-3-3epsilon isoform, may result in epilepsy and defects in learning and memory. Our research focuses on understanding the etiology of these diseases, particularly whether mutated proteins function as loss-of-function or gain-of-function proteins.

4) Development of a new medication for Parkinson’s disease – 14-3-3 modifiers.

14-3-3 proteins bind to α-Synucleins and prevent the formation of α-Synuclein inclusions. We have investigated whether 14-3-3 modifiers could prevent the formation of α-Synuclein inclusions. Additionally, we have tested which 14-3-3 isoform is most effective in preventing the formation of synuclein inclusions. We also explore chemical compounds that may have the potential to be used as 14-3-3 modifiers, which may lead to the development of new medications.

Current lab personnel:

Neetika Mishra: Undergraduate research assistant at Drexel
Christine Deng: MD student at Drexel
Lilit Drak: MD student at Drexel
Diane Kim: MS candidate at Drexel University
Samridhi Sudan: STAR scholar and an undergraduate research assistant at Drexel
Laasya Reddy Pesaladinne: High school student intern
Shiena Watanabe, MD: Postdoctoral Fellow
Vicky Shih: MD-PhD student at Drexel
William R. Telfer: MD student at Drexel
Vasu: MD student at Drexel

Past lab personnel:

Sierra Coleman: PhD candidate in Neuroscience Program
Emily Taylor: An undergraduate volunteer
Sara Shigambayeva: An undergraduate student at Drexel University
Jiwoo Lee: A high school student intern
Carrie Gordon: undergraduate student (STAR program)
Bijaya Manandhar: undergraduate student
Xiaonan Liu: PhD candidate
Cayla Andrews: MS candidate
Sarah Bennison: PhD candidate
Sara Blajezewski: PhD candidate
Lozen Robinson: undergraduate student (STAR program)
Brett T. Cornell: PhD
Thomas Sibert: MD student
Trevor Smith: research assistant
Tomoka Wachi, PhD: postdoctoral fellow

Publications

Peer-Reviewed Manuscripts

“Neuronal Morphogenesis: Methods and Protocols”
Toyo-oka, K. (Book Editor)
Methods in Molecular Biology, Springer Nature, 2024

“Ex Vivo Live Imaging in Brain Slices for Analysis of Neurite Formation in Combination with In Utero Electroporation”
Liu, X., Toyo-Oka, K.
Neuronal Morphogenesis: Methods and Protocols, Methods in Molecular Biology, 2024, 199-208

“Antagonistic Roles of Tau and MAP6 in Regulating Neuronal Development”
Sun X., Yu W., Baas P., Toyo-oka K., Qiang L.
J. Cell Sci, 2024, 137(19): jcs261966

“Localization of activity-dependent neuroprotective protein (ADNP) in neurospheres”
Bennison, S.A., Blazejewski, S.M., Liu, X., Hacohen-Kleiman, G., Sragovich, S., Zoidou, S., Touloumi, O., Grigoriadis, N., Gozes, I. and Toyo-oka, K.
Mol. Psychiatry. 2023, 28 (5), 1829

“The cytoplasmic localization of ADNP through 14-3-3 promotes sex-dependent neuronal morphogenesis, cortical connectivity, and calcium signaling”
Bennison SA, Blazejewski, SM, Liu X, Hacohen-Kleiman G, Sragovich S, Zoidou S, Touloumi O, Grigoriadis N, Gozes I and Toyo-oka K
Mol. Psychiatry. 2023, 28 (5), 1946-1959

Additional publications...

“Pyramidal neuron morphogenesis requires a septin network that stabilizes filopodia and suppresses lamellipodia during neurite initiation” Radler MR, Liu X, Peng M, Doyle B, Toyo-oka K and Spiliotis ET
Curr. Biol., 2022, 33 (3), 434-448. e8

“Nuak kinase signaling in development and disease of the central nervous system”
Bennison SA, Liu X and Toyo-oka K
Cell. Signal., (2022) 100: 110472, doi: 10.1016/j.cellsig.2022.110472

“KIFC1 regulates the trajectory of neuronal migration”
Muralidharan, H., Guha, S., Madugula, K., Patil, A., Bennison, S.A., Sun, X., Toyo-oka, K., and Baas, A.
J Neurosci., 2022, 41(11): 2149-2165

“Rpsa signaling regulates cortical neuronal morphogenesis via its ligand, PEDF, and plasma membrane interaction partner, Itga6”
Blazejewski, S.M., Bennison, S.A., Ha, N., Liu, X., Smith, T.H., Dougherty, K. J., and Toyo-oka, K.
Cereb. Cortex, 2022, 32: 770-795

“Responsible Genes for Neuronal Migration in the Chromosome 17p13.3: Beyond Pafah1b1(Lis1), Crk and Ywhae(14-3-3ε)”
Liu, X., Bennison, S.A., Robinson, L., and Toyo-oka, K.
Brain Sci. 2022, 12(1), 56

“TNFR2/14-3-3ε signaling complex instructs macrophage plasticity in inflammation and autoimmunity”
Fu, W., Hu, W., Yi, Y.-S., Hettinghouse, A., Sun, G., Bi, Y., He, W., Zhang, L., Gao, G., Liu, J., Toyo-oka, K., Xiao, G., Solit, D.B., Loke, P., and Liu, C.-J.
J. Clin. Invest. 2021, 131(16): e144016

“High-Throughput Kinase Inhibitor Screening Reveals Roles for Aurora and Nuak Kinases in Neurite Initiation and Dendritic Branching”
Blazejewski, S.M., Bennison, S.A., Liu, X. and Toyo-oka, K.
Sci Rep, 2021, 11(1):8156

“Glutathione S-transferase Pi (Gstp) Proteins Regulate Neuritogenesis in the Developing Cerebral Cortex”
Liu, X., Blazejewski, S.M., Bennison, S.A. and Toyo-oka, K.
Hum. Mol. Genet, 2021, 30(1):30-45

“Protein kinases: master regulators of neuritogenesis and therapeutic targets for axon regeneration”
Bennison SA, Blazejewski SM, Smith TH, Toyo-oka K
Cell Mol Life Sci. (2019) Oct 28. doi: 10.1007/s00018-019-03336-6

"Methionine sulfoxide reductase A (MsrA) mediates the ubiquitination of 14-3-3 protein isotypes in brain."
Deng Y, Jiang B, Rankin CL, Toyo-oka K, Richter ML, Maupin-Furlow JA, Moskovitz
J. Free Radic Biol Med. 2018, 129: 600-607.

“Neurodevelopmental Genetic Diseases Associated with Microdeletions and Microduplications of Chromosome 17p13.3”
Blajezewski SM, Bennison SA, Smith TH and Toyo-oka K
Front. Genet. 9:80 (2018) doi: 10.3389/fgene.2018.00080

“14-3-3 proteins in brain development: neurogenesis, neuronal migration and neuromorphogenesis”
Cornell B and Toyo-oka K
Front. Mol. Neurosci, 2017, 12 October 2017, https://doi.org/10.3389/fnmol.2017.00318v

"Complete ablation of the 14-3-3epsilon protein results in multiple defects in neuropsychiatric behaviors."
Wachi T, Cornell B and Toyo-oka K
Behav Brain Res, 2017, 319: 31-36.

"Deficiency of 14-3-3ε and 14-3-3ζ by the Wnt1 promoter-driven Cre recombinase results in pigmentation defects"
Cornel B and Toyo-oka K
BMC Res Notes, 9(1);180-185, 2016

"In vitro and in vivo Analysis of 14-3-3epsilon and the Regulation of Neuronal Morphogenesis via the Microtubule Binding Protein, Doublecortin."
Cornell B, Wachi T, Zhukarev V and Toyo-oka K
Hum Mole Genet, 2016, 25(20): 4405-4418.

"Overexpression of the 14-3-3Gamma Protein in Embryonic Mice Results in Neuronal Migration Delay in the Developing Cerebral Cortex"
Cornell B, Wachi T, Zhukarev V and Toyo-oka K
Neurosci Lett, in press, doi:10.1016/j.neulet.2016.06.009.

"Ablation of the 14-3-3gamma Protein Results in Neuronal Migration Delay and Morphological Defects in the Developing Cerebral Cortex"
Wachi T, Cornell B, Marshall C, Zhukarev V, Baas PW, and Toyo-Oka K
Dev Neurobiol., 76 (6): 600-614, 2016

"Novel Functions of 14-3-3 Proteins in Neurogenesis and Neuronal Differentiation In Vivo"
Wachi T and Toyo-oka K
Ther Targets Neurol Dis (Therapeutic targets for neurological diseases), 2015, 2(1), doi: 10.14800/ttnd.500

"14-3-3epsilon and zeta Regulate Neurogenesis and Differentiation of Neuronal Progenitor Cells in the Developing Brain""
Toyo-oka K, Wachi T, Hunt RF, Baraban SC, Taya S, Ramshaw H, Kaibuchi K, Schwarz QP, Lopez AF and Wynshaw-Boris A
J Neurosci., 34(36):12168-12181, 2014

"14-3-3{varepsilon} Plays a Role in Cardiac Ventricular Compaction by Regulating the Cardiomyocyte Cell Cycle"
Kosaka Y, Cieslik KA, Li L, Lezin G, Maguire CT, Saijoh Y, Toyo-Oka K, Gambello MJ, Vatta M, Wynshaw-Boris A, Baldini A, Yost HJ and Brunelli L
Mol. Cell. Biol., 32:5089-5102, 2012

"Neurodevelopmental defects and neuropsychiatric behaviour arise from 14-3-3zeta deficiency"
Cheah PS, Ramshaw HS., Thomas PQ, Toyo-oka K, Martin S, Coyle P, Guthridge MA, Stomski F, van den Buuse M, Wynshaw-Boris A, Lopez AF and Schwarz QP
Mol. Psychiatr., 17:451-466, 2011

"Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia"
Ikeda M, Hikita T, Taya S, Uraguchi-Asaki J, Toyo-oka K, Wynshaw-Boris A, Ujike H, Inada T, Takao K, Miyakawa T, Osaki N, Kaibuchi K and Iwata N
Hum. Mol. Genet., 17: 3212-3222, 2008

"A Neuroepithelial Stem Cell Proliferation requires LIS1 for Precise Spindle Orientation and Symmetric Division"
Yingling J, Youn YH, Darling D, Toyo-oka K, Pramparo T, Hirotsune S and Wynshaw-Boris
Cell, 132: 474-486, 2008

"Protein Phosphatase4 catalytic subunit (PP4c) regulates CDK1 activity and organization of microtubules through dephosphorylation of NDEL1"
Toyo-oka K, Yano Y, Shiota M, Iwao H, Hiraiwa N, Muramatsu M, Yoshiki A and Hirotsune S
J Cell Biol., 180: 1133-1147, 2008

"NDEL1 Phosphorylation by Aurora-A Kinase Is Essential for Centrosomal Maturation, Separation, and TACC3 recruitment"
Mori D, Yano Y, Toyo-oka K, Yoshida N, Yamada M, Muramatsu M, Zhang D, Saya H, Toyoshima YY, Kinoshita K, Wynshaw-Boris A and Hirotsune S
Mol. Cell. Biol., 27: 352-367, 2007

"Mnt-Deficient Mammary Glands Exhibit Impaired Involution and Tumors with Characteristics of Myc Overexpression"
Toyo-oka K, Bowen TJ, Hirotsune S, Li Z, Jain S, Ota S, Lozach LE, Bassett IG, Lozach J, Rosenfeld MG, Glass CK, Eisenman R, Ren B, Hurlin PJ and Wynshaw-Boris A
Cancer Res., 66: 5565-5573, 2006

"Recruitment of katanin P60 by phosphorylated NDEL1, an LIS1 interacting protein, is essential for mitotic cell division and neuronal migration"
Toyo-oka K, Sasaki S, Yano Y, Mori D, Kobayashi T, Toyoshima YY, Tokuoka SM, Ishii S, Shimizu T, Muramatsu M, Hiraiwa N, Yoshiki A, Wynshaw-Boris A and Hirotsune S
Hum. Mol. Genet., 14: 3113-3128, 2005

"Complete Loss of Ndel1 Results in Neuronal Migration Defects and Early Embryonic Lethality"
Sasaki S, Mori D, Toyo-oka K, Chen A, Garrett-Beal L, Muramatsu M, Miyagawa S, Hiraiwa N, Yoshiki A, Wynshaw-Boris A, and Hirotsune A
Mol. Cell. Biol., 25:7812-7827, 2005

"Loss of the Max-interacting protein Mnt in mice results in decreased viability, defective embryonic growth and craniofacial defects: relevance to Miller-Dieker syndrome"
Toyo-oka K, Hirotsune S, Gambello MJ, Zhou Z-Q, Olson L, Rosenfeld MG, Eisenman R, Hurlin PJ and Wynshaw-Boris A
Hum. Mol. Genet., 13:1057-1067, 2004

"Evidence of Mnt-Myc Antagonism Revealed by Mnt Gene Deletion"
Hurlin PJ, Zhou Z-Q, Toyo-oka K, Ota S, Walker WL, Hirotsune S and Wynshaw-Boris A
Cell Cycle, 3:97-99, 2004

"Deletion of Mnt leads to disrupted cell cycle control and tumorigenesis"
Hurlin PJ, Zhou Z-Q, Toyo-oka K, Ota S, Walker WL, Hirotsune S and Wynshaw-Boris A
EMBO J., 22:4584-4596, 2003

"Miller-Dieker Syndrome: Analysis of a Human Contiguous Gene Syndrome in the Mouse"
Yingling J, Toyo-oka K, and Wynshaw-Boris A
Am. J. Hum. Genet., 73(3):475-488, 2003

"14-3-3epsilon is important for neuronal migration via binding of NUDEL : a molecular explanation for Miller-Dieker syndrome"
Toyo-oka K, Shionoya A, Gambello MJ, Cardoso C, Leventer R, Ward HL, Ayala R, Tsai L-H, Dobyns W, Ledbetter D, Hirotsune S and Wynshaw-Boris A
Nat. Genet., 34:274-285, 2003

"Refinement of a 400-kb Critical Region Allows Genotypic Differentiation between Isolated Lissencephaly, Miller-Dieker Syndrome, and Other Phenotypes Secondary to Deletions of 17p13.3"
Cardoso C, Leventer RJ, Ward HL, Toyo-oka K, Chung J, Gross A, Martin CL, Allanson J, Pilz DT, Olney AH, Mutchinick OM, Hirotsune S, Wynshaw-Boris A, Dobyns WB and Ledbetter DH
Am. J. Hum. Genet., 72:918-930, 2003

Contact Information

kt469@drexel.edu

Department of Neurobiology & Anatomy
2900 W. Queen Lane, Room 186
Philadelphia, PA 19129
Phone: 215.991.8288