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Takaki Miyata MD, Ph DProfessor, Department of Cell Biology, Nagoya University Graduate School of Medicine

Specialized field

Neural Development, Brain Formation

Career Summary

2004/1- present:
Professor, Department of Anatomy and Cell Biology, Nagoya University Graduate School of Medicine, Japan
Research Scientist, Laboratory for Cell Culture Development (Dr. Masaharu Ogawa’s lab), Brain Science Institute, RIKEN, Japan
Research Associate, Department of Neuroanatomy (Dr. Hideyuki Okano’s lab, Osaka University Graduate School of Medicine, Japan
Postdoctoral Fellow, Department of Molecular, Cellular, and Developmental Biology (Dr. Jacqueline Lee's Lab), University of Colorado at Boulder, Colorado, USA
Postdoctoral Fellow, Department of Molecular Neurobiology (Dr. Katsuhiko Mikoshiba's Lab), Institute for Medical Science, University of Tokyo, Japan
Postdoctoral Fellow, Molecular Neurobiology Laboratory (Dr. Katsuhiko Mikoshiba's Lab), Tsukuba Life Science Center, RIKEN, Japan
Graduate Student, Department of Physiology, Kochi Medical School, Japan (supervised by Dr. Masaharu Ogawa)
Department of Otolaryngology and Head and Neck Surgery (Prof. Haruo Saito), Kochi Medical School Hospital

Research Theme

Studying molecular and cellular mechanisms of the brain formation

Research Summary

Title of research: Elucidation of molecular and cellular mechanisms underlying the formation of the neocortex and cerebellum

A. Purposes
(1) We are asking how neural stem cells’ morphology is regulated and how this regulation contributes to the overall brain formation. Stem/progenitor cells in the mammalian brain primordia originally take a neuroepithelial structure in which their nuclei/somata diffusely occupy the entire wall of neural tube or brain vesicle (about ten nuclei thick). This diffuse nuclear distribution is due to the cell cycle-dependent, interkinetic nuclear migration (INM) exhibited by each of the neuroepithelial cells (80 μm long) that span from the apical (inner/ventricular) surface to the basal (outer/pial) surface of the wall. When the first neuronal group comes out as a result of divisions within the initial neuroepithelium, neurons accumulate in an outer zone (1-2 cell thick) just beneath the basal lamina and stem/progenitor cells become longer (90-100 μm) while keeping their apicobasal attachment as well as nuclear migration trajectory in a range of 80 μm (ten nuclei thick) and having elaborated a basal/pial process (~20 μm). How this elongation occurs is unknown and it is important to understand how this phenomenon might affect stem/progenitor cells’ cytogenetic behavior.
(2) Microtubule organization plays a key role in neuronal migration and axon/dendrite formation during the brain morphogenesis. To study the organization of microtubules in neuronal migration and axon formation in situ, we monitored dynamics of centrosome and microtubule plus-ends in migrating neurons in the developing neocortex.

B. Results
(1) Through in utero electroporation-mediated RNAi experiments and live imaging in slice culture, we found that the earliest cohort of neurons in developing mouse neocortex may play an important role in shaping the neural stem/progenitor cells. Acute dysfunction of the neocortical subplate neurons (born during embryonic day [E]10-E11) resulted in the loss of stem cells’ elongation by E12 and abnormal territorialization of neuronal and stem cells’ nuclei/somata by E13, which further caused massive histogenetic errors by E15. In summary, we found that (i) the basal process is essential for the early neocortical progenitor cells’ INM, especially for nuclear/somal migration away from the ventricular surface, (ii) normal INM underlies the ordered territorialization between VZ and neuronal zones, thereby contributing to the overall neocortical histogenesis, and (iii) subplate neurons, which have long been known for their late embryonic roles in connecting the neocortex and thalamus, also play an important role during the earliest stage of neocorticogenesis in shaping the neural progenitor cells (Okamoto et al., manuscript in preparation).
(2) We first found that centrosome tends to move toward the most dominantly growing process in migrating neurons; leading process dominantly acts on centrosome positioning than trailing process. Centrosome at the base of leading process was occasionally overtaken by rapidly translocating nucleus, suggesting the importance of a nucleokinesis mechanism that is not affected by a local change of the microtubule organization. Although the centrosome proximity has been implicated in the initiation of certain types of axons, our observation suggests that it is not important for backward initiation of axon by migrating neocortical pyramidal neurons (Sakakibara et al., manuscript submitted).

Principal Research Achievement

  1. Miyata T: Neural Development, Preface. Dev Growth Differ, in press (2012)
  2. Xie M, Yagi H, Kuroda K, Wang C, Komada M, Zhao H, Sakakibara A, Miyata T, Nagata K, Iguchi T, Sato M: WAVE2-Abi2 complex controls growth cone activity and regulates the multipolar-bipolar transition as well as the initiation of glia-guided migration. Cerebral Cortex, in press (2012)
  3. Natsume A, Kato T, Kinjo S, Enomoto A, Toda H, Shimato S, Ohka F, Motomura K, Kondo Y, Miyata T, Takahashi M, Wakabayashi T: Girdin maintains the stemness of glioblastoma stem cells. Oncogene, in press (2011)
  4. Nakamuta S, Funahashi Y, Namba T, Arimura N, Picciotto MR, Tokumitsu H, Soderling TR, Sakakibara A, Miyata T, Kamiguchi H, Kaibuchi K: Local application of neurotrophins specifies axons through inositol 1,4,5-trisphosphate, calcium, and Ca2+/calmodulin-dependent protein kinases. Sci Signal, 4, ra76 (2011)
  5. Wang Y, Nakayama M, Pitulescu ME, Schmidt TS, Bochenek ML, Sakakibara A, Adams S, Davy A, Deutsch U, Luthi U, Barberis A, Benjamin LE, Makinen T, Nobes CD, Adams RH: Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis. Nature, 465, 483-486 (2010)
  6. Miyata T, Ono Y, Okamoto M, Masaoka M, Sakakibara A, Kawaguchi A, Hashimoto M, Ogawa M: Migration, early axonogenesis, and Reelin-dependent layer-forming behavior of early/posterior-born Purkinje cells in the developing mouse lateral cerebellum. Neural Dev, 5, 23 (2010)
  7. Miyata T, Kawaguchi D, Kawaguchi A, Gotoh Y. Mechanisms that regulate the number of neurons during mouse neocortical development. Curr Opin Neurobiol, 20, 22-28 (2010)
  8. Uchida T, Baba A, Perez-Martinez FJ, Hibi T, Miyata T, Luque JM, Nakajima K, Hattori M. Downregulation of functional Reelin receptors in projection neurons implies that primary Reelin action occurs at early/premigratory stages. J Neurosci, 29, 10653-10662 (2009)
  9. Saito K, Dubreuil V, Arai Y, Wilsch-Bruninger M, Schwudke D, Saher G, Miyata T, Breier G, Thiele C, Shevchenko A, Nave KA, Huttner WB. Ablation of cholesterol biosynthesis in neural stem cells increases their VEGF expression and angiogenesis but causes neuron apoptosis. Proc Natl Acad Sci USA, 106, 8350-8355 (2009)
  10. Minobe S, Sakakibara A, Ohdachi T, Kanda R, Kimura M, Nakatani S, Tadokoro R, Ochiai W, Nishizawa Y, Mizoguchi A, Kawauchi T, Miyata T. Rac is involved in the interkinetic nuclear migration of cortical progenitor cells. Neurosci Res, 63, 294-301 (2009)
  11. Ochiai W, Nakatani S, Takahara T, Kainuma M, Masaoka M, Minobe S, Namihira M, Nakashima K, Sakakibara A, Ogawa M, Miyata T. Periventricular Notch activation and asymmetric Ngn2 and Tbr2 expression in pair-generated neocortical daughter cells. Mol Cell Neurosci, 40, 225-233 (2009)
  12. Yoon K-J, Koo B-K, Jeong H-W, Ghim J, Kwon M-C, Moon J-S, Miyata T, Kong Y-Y. Mind bomb 1-experssing intermediate progenitors generate Notch signaling to maintain radial glial cells. Neuron, 58, 519-531 (2008)
  13. Sunabori T, Tokunaga A, Nagai T, Sawamoto K, Okabe M, Miyawaki A, Matsuzaki Y, Miyata T, Okano H. Cell-cycle-specific nestin expression coordinates with morphological changes in embryonic cortical neural progenitors. J Cell Sci, 121, 1204-1212 (2008)
  14. Miyata T. Development of three-dimensional srchitecture of the neuroepithelium: Role of pseudostratification and cellular 'community'. Dev Growth Differ, 50, S105-S112 (2008)
  15. Sakaue-Sawano A, Kurokawa H, Morimura T, Hanyu A, Hama H, Osawa H, Kashiwagi S, Fukami K, Miyata T, Miyoshi H, Imamura T, Ogawa M, Masai H, Miyawaki A. Visualizing spatiotemporal dynamics of multicellular cell-cycle Progression. Cell, 132, 487-498 (2008)
  16. Konno D, Shioi G, Shitamukai A, Mori A, Kiyonari H, Miyata T, Matsuzaki F. Neuroepithelial progenitors undergo LGN-dependent planar divisions to maintain self-renewability during mammalian neurogenesis. Nat Cell Biol, 10, 93-101 (2008)
  17. Kawaguchi A et al. Single-cell gene profiling defines differential progenitor subclasses in mammalian neurogenesis. Development 135: 3113-3124 (2008)
  18. Miyata T et al. Twisting of neocortical progenitor cells underlies a spring-like mechanism for daughter cell migration. Curr. Biol. 17: 146-151 (2007)
  19. Tamai H et al. Pax6 transcription factor is required for the interkinetic nuclear movement of neuroepithelial cells. Genes Cells 12: 983-996 (2007)
  20. Sakakibara A et al. Mechanism of polarized protrusion formation on neuronal precursors migrating in the developing chicken cerebellum. J. Cell Sci. 119: 3583-3592 (2006)
  21. Hirai S et al. The c-Jun N-terminal kinase activator dual leucine zipper kinase regulates axon growth and neuronal migration in the developing cerebral cortex. J. Neurosci. 26: 11992-12002 (2006)
  22. Imai F et al. Inactivation of aPKCl results in the loss of adherens junctions in neuroepithelial cells without affecting neurogenesis in mouse neocortex. Development 133: 1735-1744 (2006)
  23. Naruse M et al. Induction of oligodendrocyte progenitors in dorsal forebrain by intraventricular microinjection of FGF-2. Dev. Biol. 60: 1084-1100 (2006)
  24. Kawaguchi A et al. Differential expression of Pax6 and Ngn2 between pair-generated cortical neurons. J. Neurosci. Res. 78: 784-795 (2004)
  25. Miyata T et al. Asymmetric production of surface-dividing and non-surface-dividing cortical progenitor cells. Development 131: 3133-3145 (2004)
  26. Shinozaki K et al. Absence of Cajal-Retzius cells and subplate neurons associated with defects of tangential migration from ganglionic eminence in Emx1/2 double mutant cerebral cortex. Development 129: 3479-3492 (2002)
  27. Miyata T et al. Asymmetric inheritance of radial glial fibers by cortical neurons. Neuron 31: 727-741 (2001)
  28. Kawaguchi A et al. Nestin-EGFP mice: visualization of the self-renewal and multipotency of CNS stem cells. Mol. Cell. Neurosci.17: 259-273 (2001)
  29. Nakamura Y et al. The bHLH gene Hes1 as a repressor of neuronal commitment of the CNS stem cells. J. Neurosci. 20: 283-293 (2000)
  30. Miyata T et al. NeuroD is required for differentiation of the granule cells in the cerebellum and hippocampus. Genes & Dev. 13: 1647-1652 (1999)
  31. Miyata T et al. Regulation of Purkinje cell alignment by Reelin as revealed with CR-50 antibody. J. Neurosci. 17: 3599-3609 (1997)
  32. Del Rio J et al. A role for Cajal-Retzius cells and reelin in the development of hippocampal connections. Nature 385: 70-74 (1997)
  33. Ogawa M et al. The reeler gene-associated antigen on Cajal-Retzius neurons is a crucial molecule for laminar organization of cortical neurons. Neuron 14: 899-912 (1995)