Laboratory/Faculty

Laboratory of Genetic Mechanisms
Group of Cell Regulation

ProfessorMakoto Kinoshita
Cytoskeleton-mediated phenotypic regulation and disease susceptibility
LecturerNatsumi Ageta-Ishihara
Neural activity-dependent regulation of neuronal/glial architecture and function
Assistant ProfessorAsako Shindo
Cytoskeleton-driven collective cellular reorganization for organogenesis and tissue repair
▶Laboratory HP
Japanese
Makoto Kinoshita Professor
Lab members

Unraveling the mysteries of life through the mysterious cytoskeleton

A common goal of science is the elucidation of the principles underlying self-organization of complex systems. In life science, a class of self-assembling protein polymers termed the cytoskeleton is central to this goal, because the cytoskeleton is the major determinant of cell shape and force. The actin ATPases and the tubulin GTPases, along with their counterpart motor proteins, have been well studied as key cytoskeletal components; however, the characteristics and functions of the septin GTPases remain elusive.

Due to their fundamental importance, either excess or deficiency of cytoskeletal proteins can affect cell shape and functions. Unless compensated, the cellular malfunctions manifest at the organismal level as lethality, morphological anomalies and/or functional defects. Such defects provide precious hints that help us understand complex biological systems, and hopefully control human diseases, e.g., neuropsychiatric disorders, neoplasia, infertility, infection.

Our approach is a combination of mouse reverse genetics, cell biology and biochemistry. First, we generate knockout or transgenic mice that lack or overexpress septins and/or related cytoskeletal regulators. Second, we explore defects (e.g., morphology, physiology including behavior, disease susceptibility) of these mice by multimodal screening. Third, we define the underlying molecular mechanisms of given defects via reductionistic (cell- , protein- and gene-based) approaches. By focusing on the mysteries of the cytoskeleton, we seek clues to unravel the mysteries of life.

Fig.1

Diversity of higher-order septin assembly reconstituted in vitro. 1) Circular self-assembly. 2) Phospholipid-templated assembly, which can reshape the membrane. 3) Actomyosin-templated assembly, which may stabilize the contractile ring and stress fibers.

Fig.2

Samples of diverse septin organizations and our approach. (From left) Ultrastructural analysis of septin clusters that organize membrane subdomains. Morphometry of developing neurons. The flagellar septin rings (green) in spermatozoa, discovered by reverse genetics. The septin cuffs (red) at the glia-neuron interface. Mouse genotyping at a glance.

References

  1. Shindo A. and Wallingford J.B. (2014) Science, 343:649-652.
  2. Ageta-Ishihara N. et al. (2013) Nature Communications, 4:2532.
  3. Ageta-Ishihara N. et al. (2013) Molecular Brain, 6:35.
  4. Yanagida A. et al. (2011) BBA Molecular Basis of Disease, 812:1403-1411.
  5. Hagiwara A. et al. (2011) Cytoskeleton, 68:512-525.
  6. Kim S.K., Shindo A. et al. (2010) Science, 329:1337-1340.
  7. Tanaka-Takiguchi Y. et al. (2009) Current Biology, 19:140-145.
  8. Tooley AJ. et al. (2009) Nature Cell Biology, 11:17-26.
  9. Iwaisako K. et al. (2008) Journal of Hepatology, 49:768-778.
  10. Ihara M. et al. (2007) Neuron, 53:519-533.
  11. Ihara M. et al. (2005) Developmental Cell, 8:343-352.
  12. Spiliotis ET. et al. (2005) Science, 307:1781-1785.
  13. Kinoshita M. et al. (2002) Developmental Cell, 3:791-802.
  14. Kinoshita M. et al. (1997) Genes and Development, 11:1535-1547.

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