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.
Highlights
Undifferentiated neural progenitor cells (NPCs) are central to the production of a variety of cells in developing and mature brains [1,2,3,4,5,6,7,8,9]
We found that artificial activation of Yap/TEA domain (Tead) enhanced NPC self-renewal in both telencephalic and diencephalic NE/ventricular zone (VZ), whereas NPC heterotopias formed much more frequently in the diencephalon than in the telencephalon
Observation of sections immunostained with anti-Yes-associated protein 1 (Yap1) antibody at low magnification revealed intense Yap1 immunoreactivity in the NE and VZ of both regions, which were positive for Pax6 (Fig. 1a, b)
Summary
Undifferentiated neural progenitor cells (NPCs) are central to the production of a variety of cells in developing and mature brains [1,2,3,4,5,6,7,8,9]. We performed IUE at embryonic day 10 (E10), because (1) the forebrain primordium at this early stage is similar to the neural tube in terms of the composition and structure of the NE, and (2) in previous work, the use of the same protocol to activate Wnt3a induced mild NPC heterotopias in the telencephalon [14], allowing us to comparatively address possible contributions of Yap/Tead in NPC heterotopia formation.
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