Laboratories

Systems Neurobiology and Medicine

Outline of Research and Education

Neurons extend long processes, axons, and form elaborate networks in our brain; all our brain activity depends on these neuronal networks. Axons decide their migratory route in response to gradients of chemical signals with extraordinary sensitivity. Such a paradigm was proposed over a century ago (1890) by the prominent neuroscientist Santiago Ramón y Cajal, but little is known about how axons are able to decide their migratory routes by reading subtle gradients of chemical signals and by translating them into directional driving force.

In addition to axons, various cells migrate within our body, thereby playing key roles in forming the body and organs as well as in immune responses, wound healing and regeneration. Disruption of cell migration is implicated in diseases, including birth abnormality, neuronal disabilities, immune disorders and cancer metastasis.

Our laboratory focuses on cell morphogenesis and the proteins Shootin1a, Shootin1b and Singar1, which we identified via proteome analyses. We analyze the molecular mechanisms for axon guidance, cell migration, neuronal polarization and synaptogenesis, using up-to-date methods including systems biology and mechanobiology. We also analyze actin waves which represent a new type of intracellular protein transport system for cell morphogenesis.

We expect that these analyses will help us to understand the mechanisms underlying diseases including birth abnormality, neuronal disabilities, and immune disorders, giving us a new window into therapeutic strategies for nerve injury, Alzheimer’s disease and cancer metastasis.

Major Research Topics

Axon/dendrite formation, neuronal polarization and migration

The basic function of neurons is to receive signals, integrate them and transmit them to the next neuron. Thus, neurons can function as semiconductors in the brain. Neuronal polarity plays an essential role for this function. Namely, most of neurons form a single axon and multiple dendrites. Dendrites receive signals from outside, while an axon output signals. Then a signal flow arises from dendrites via cell body to the axon. How neurons acquire neuronal polarity? Our lab investigates the mechanism for axon/dendrite formation and neuronal polarization, focusing on shootin and singar (Toriyama et al., 2006; Mori et al., 2007), as well as their interacting proteins. We are also analyzing how neurons polarize in order to migrate.

Generation of mechanical forces for axon guidance and cell migration

Animals move and change their shape, using force generated by muscles. How cells do so? Actin polymerizes near the leading edges of neurite tips and migrating cells. Our studies showed that shootin1 interacts with both the polymerizing actin filaments and L1-CAM at neurite tips, thereby generating traction force for neurite outgrowth (Shimada et al., 2008). We are currently analyzing such linker molecules (“Clutch” molecules) to understand the molecular mechanisms for force generation for axon guidance and cell migration. (Toriyama et al., 2013; Kubo et al., 2015; Abe et al., 2018; Baba et al., 2018).

Actin waves: novel mechanisms for intracellular protein transport

We are also analyzing actin waves which represent a new type of intracellular protein transport system for cell polarization and migration (Toriyama et al., 2010; Katsuno et al., 2015; Inagaki and Katsuno, 2017).

Crux of biological morphogenesis: Symmetry breaking

Biological systems self-organize their simple shape into more complicated ones in a universe that continuously increase disorder (entropy). Symmetry breaking is an essential step of such miraculous biological morphogenesis. As an example, neurons break their symmetry by elongating a single long axon and multiple short dendrites: symmetry breaking is the initial step of neuronal polarity formation. One advantage of neurons over other types of cells is that their morphology can be described in simple terms using a small number of variables for neurite length (see left). Using a combination of quantitative live cell imaging and mathematical modeling, we are analyzing the mechanisms involved in neuronal symmetry breaking. Our data suggest that the abovementioned length-dependent shootin1 accumulation and shootin1-dependent neurite outgrowth constitutes a positive feedback loop that amplifies stochastic fluctuations of shootin1 signals, thereby leading to spontaneous neuronal symmetry-breaking (Toriyama et al., 2010; Inagaki et al., 2010).

References

  1. Abe et al., PNAS, 115, 2764-2769, 2018
  2. Baba et al., eLife, 7, e34593, 2018
  3. Inagaki and Katsuno, Trends Cell Biol., 27, 515-526, 2017
  4. Higashiguchi et al., Cell Tissue Res., 366, 75-879, 2016
  5. Toriyama M. et al., Nature Genetics, 48, 648–656, 2016
  6. Katsuno H. et al., Cell Rep., 12, 648-660, 2015
  7. Kubo Y. et al., J. Cell Biol., 210, 663-676, 2015
  8. Toriyama M. et al., Curr. Biol. , 23,529-534, 2013
  9. Nakazawa H. et al., J. Neurosci., 32, 12712-12725, 2012
  10. Inagaki N. et al., Dev. Neurobiol., 71, 584-593, 2011
  11. Toriyama M. et al., Mol. Syst. Biol., 6, 394, 2010
  12. Shimada T. et al., J. Cell Biol., 181, 817-829, 2008
  13. Mori T. et al., J. Biol. Chem., 282, 19884-19893, 2007
  14. Toriyama M. et al., J. Cell Biol., 175, 147-157, 2006
  15. Nomura E. et al., J. Mass Spectrometry, 39, 666-672, 2004
  16. Oguri T. et al., Proteomics, 2, 666-672, 2002
  17. Fukata Y. et al., Nature Cell Biol., 4, 583-591, 2002
  18. Inagaki N. et al., Nature Neurosci., 4, 872-873, 2001
Fig.1
Fig.1 Shootin1 is a key molecule involved in neuronal symmetry breaking
Fig.2
Fig.2 Singar knockdown leads to formation of surplus axons
Fig.3
Fig.3 An equation to describe neurite length sensing by shootin1
Fig.4
Fig.4 Signal-force transduction through shootin phosphorylation at growth cones
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