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Regulatory Mechanism of Neural Progenitor Cells Revealed by Optical Manipulation of Gene Expressions

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Neural stem/progenitor cells are multipotent and self-renewable cells that can give generate neurons, astrocytes, and oligodendrocytes. These processes are controlled by multiple basic-helix-loop-helix (bHLH) transcription factors. bHLH transcription factors also regulate direct reprogramming of adult somatic cells into neurons and oligodendrocytes. Thus, bHLH factors play pivotal roles in development and regeneration of the nervous system. Here, we review essential functions of bHLH factors, especially focusing on the regulatory mechanism through the dynamic expression changes. To precisely analyze the functional roles of dynamic gene expression changes, tools that manipulate gene expression at fine temporal and spatial resolution are needed. We also review novel strategies to optically manipulate gene expression dynamics in neural progenitor cells.


  • bHLH transcription factor
  • Neural progenitor cells
  • Gene expression
  • Oscillation
  • Optogenetics

The basic-helix-loop-helix (bHLH) transcription factors Hes1, Ascl1/Mash1 and Olig2 facilitate the fate determination of astrocytes, neurons and oligodendrocytes, respectively (Imayoshi and Kageyama 2014). However, these bHLH transcription factors are co-expressed in multipotent self-renewing neural progenitor cells even before cell fate choice (Imayoshi et al. 2013). This finding indicates that these fate determination factors are differentially expressed between self-renewing and differentiating neural progenitor cells with unique expression dynamics. Live imaging analysis with fluorescent and bioluminescent proteins is a powerful strategy for monitoring expression dynamics. Our imaging results indicate that bHLH transcription factors are expressed in an oscillatory manner by neural progenitor cells, and that one of them becomes dominant in fate choice. We propose that the multipotent state of neural progenitor cells correlates with the oscillatory expression of several bHLH transcription factors, whereas the differentiated state correlates with the sustained expression of a single bHLH transcription factor.

To address the cousal relationships between the expression dynamics (oscillatory versus sustained) and functional outcomes (cell proliferation versus fate differentiation), the optogenetic approach has been employed to control the expression patterns of bHLH transcription factors (Imayoshi et al. 2013). We applied a novel optogenetic method (photo-activatable Gal4/UAS system) to manipulate the expression patterns of bHLH transcription factors using blue light illumination, showing that oscillatory expression activates the cell proliferation of neural progenitor cells, whereas sustained expression induces cell fate determination (Fig. 2.1).

Fig. 2.1
figure 1

Expression dynamics of bHLH factors in multipotency and cell fate determination. (This figure was modified from Figure 5 of Imayoshi and Kageyama 2014)


  • Imayoshi I, Isomura A, Harima Y, Kawaguchi K, Kori H, Miyachi H, Fujiwara T, Ishidate F, Kageyama R (2013) Oscillatory control of factors determining multipotency and fate in mouse neural progenitors. Science 342:1203–1208

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  • Imayoshi I, Kageyama R (2014) bHLH factors in self-renewal, multipotency, and fate choice of neural progenitor cells. Neuron 82:9–23

    CAS  CrossRef  Google Scholar 

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Correspondence to Itaru Imayoshi .

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Imayoshi, I., Yamada, M., Suzuki, Y. (2020). Regulatory Mechanism of Neural Progenitor Cells Revealed by Optical Manipulation of Gene Expressions. In: Toyama, Y., Miyawaki, A., Nakamura, M., Jinzaki, M. (eds) Make Life Visible. Springer, Singapore.

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