Laboratories

Systems Neurobiology and Medicine

Outline of Research and Education

During morphogenesis, biological systems self-organize their simple shapes into more complicated and beautiful ones. The goal of our studies is to understand deeply this miraculous phenomenon of cellular morphogenesis. There are fundamental questions to be answered. Symmetry breaking (change of a symmetric shape to an asymmetric one) is an essential process of morphogenesis: theoretical models suggest that feedback loops and lateral inhibition may be involved, but how do cellular molecules indeed give rise to these processes? Generation of mechanical forces is required to create cellular shape, but how? How do cells sense cellular length and size in order to regulate their size and morphology? Transport and diffusion of intracellular molecules would create inhomogeneous distribution: Do they play a role in cellular pattern formation? Is stochasticity utilized in cellular morphogenesis? All these questions are fascinating to us.

To untangle these issues, our laboratory focuses on neuronal morphogenesis and the proteins Shootin1a, Shootin1b and Singar1, which we identified via proteome analyses. We analyze the molecular mechanisms for cell migration, neuronal polarization, axon guidance and synaptogenesis, using up-to-date methods including systems biology and mechanobiology. We expect that these analyses will give 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 neuronal 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 neurite outgrowth and cell migration.

Sensing of cellular length and size

Correct control of size and morphology is essential for cells to function properly. In contrast to the progress in understanding the molecular signals that change cell morphologies, the manner in which cells check their size and length to regulate their morphology is poorly understood. Recently we found that shootin1 accumulates in neurite tips in a neurite length-dependent manner (Toriyama et al., 2010; Inagaki et al., 2010). Thus, morphologicalinformation, neurite length, is translated into a molecular signal (shootin1 concentration in neurite tips). Live cell imaging combined with mathematical analyses further demonstrated that the neurite length-dependent shootin1 accumulation is quantitatively explained by its anterograde transport and retrograde diffusion.

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 (Craig and Banker, Annu Rev Neurosci 17:267-31, 1994; Yamasaki et al, J Neurosci 30:15221-7, 2010): 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. Higashiguchi et al., Cell Tissue Res, 2016, DOI: 10.1007/s00441-016-2415-9
  2. Toriyama M. et al., Nature Genetics 48, 648–656, 2016
  3. Katsuno H. et al., Cell Rep., 12, 648-660, 2015
  4. Kubo Y. et al., J. Cell Biol., 210, 663-676, 2015
  5. Toriyama M. et al., Curr. Biol. , 23,529-534, 2013
  6. Nakazawa H. et al., J. Neurosci., 32, 12712-12725, 2012
  7. Inagaki N. et al., Dev. Neurobiol., 71, 584-593, 2011
  8. Toriyama M. et al., Mol. Syst. Biol., 6, 394, 2010
  9. Shimada T. et al., J. Cell Biol., 181, 817-829, 2008
  10. Urasaki A. et al., PNAS, 105, 19827-19832, 2008
  11. Mori T. et al., J. Biol. Chem., 282, 19884-19893, 2007
  12. Toriyama M. et al., J. Cell Biol., 175, 147-157, 2006
  13. Urasaki A. et al., Genetics, 174, 639-649, 2006
  14. Nomura E. et al., J. Mass Spectrometry, 39, 666-672, 2004
  15. Oguri T. et al., Proteomics, 2, 666-672, 2002
  16. Fukata Y. et al., Nature Cell Biol., 4, 583-591, 2002
  17. 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
Back to Top