Neural Progenitor Cells Undergoing Yap/Tead-Mediated Enhanced Self-Renewal Form Heterotopias More Easily in the Diencephalon than in the Telencephalon

Abstract

Spatiotemporally ordered production of cells is essential for brain development. Normally, most undifferentiated neural progenitor cells (NPCs) face the apical (ventricular) surface of embryonic brain walls. Pathological detachment of NPCs from the apical surface and their invasion of outer neuronal territories, i.e., formation of NPC heterotopias, can disrupt the overall structure of the brain. Although NPC heterotopias have previously been observed in a variety of experimental contexts, the underlying mechanisms remain largely unknown. Yes-associated protein 1 (Yap1) and the TEA domain (Tead) proteins, which act downstream of Hippo signaling, enhance the stem-like characteristics of NPCs. Elevated expression of Yap1 or Tead in the neural tube (future spinal cord) induces massive NPC heterotopias, but Yap/Tead-induced expansion of NPCs in the developing brain has not been previously reported to produce NPC heterotopias. To determine whether NPC heterotopias occur in a regionally characteristic manner, we introduced the Yap1-S112A or Tead-VP16 into NPCs of the telencephalon and diencephalon, two neighboring but distinct forebrain regions, of embryonic day 10 mice by in utero electroporation, and compared NPC heterotopia formation. Although NPCs in both regions exhibited enhanced stem-like behaviors, heterotopias were larger and more frequent in the diencephalon than in the telencephalon. This result, the first example of Yap/Tead-induced NPC heterotopia in the forebrain, reveals that Yap/Tead-induced NPC heterotopia is not specific to the neural tube, and also suggests that this phenomenon depends on regional factors such as the three-dimensional geometry and assembly of these cells.

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Abbreviations

BrdU:

Bromodeoxyuridine

CNS:

Central nervous system

E:

Embryonic day

IKNM:

Interkinetic nuclear migration

IUE:

In utero electroporation

NE:

Neuroepithelium

NPC:

Neural progenitor cell

Tead:

TEA domain transcription factor

VZ:

Ventricular zone

Yap1:

Yes-associated protein 1

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Acknowledgements

We thank Namiko Noguchi, Kumiko Ota, Maiko Kuroda and Makoto Masaoka for excellent technical assistance, and members of Miyata laboratory for discussion. This work was supported by MEXT KAKENHI 22111006 (T.M.), JSPS KAKENHI 16H02457 (T.M.), JSPS KAKENHI 16K06990 (A.K.) and Grant-in-Aid for JSPS Research Fellow (K.S.).

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Correspondence to Takaki Miyata.

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Kanako Saito and Ryotaro Kawasoe have contributed equally to this work.

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Saito, K., Kawasoe, R., Sasaki, H. et al. Neural Progenitor Cells Undergoing Yap/Tead-Mediated Enhanced Self-Renewal Form Heterotopias More Easily in the Diencephalon than in the Telencephalon. Neurochem Res 43, 180–189 (2018). https://doi.org/10.1007/s11064-017-2390-x

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Keywords

  • Neural progenitor cells
  • Ventricular zone
  • Self-renewal
  • Yap
  • Tead
  • Heterotopia