Regulation of mammalian neural development via cell death signaling

Many cells die during development. To reveal physiological significance of cell death, we are mainly focusing on the nervous system development in which a lot of cell death are observed. Dysregulation of apoptosis leads to cranial NTC defects like exencephaly, although the mechanism is unclear. Observing cells undergoing apoptosis in a living context could help elucidate their origin, behavior, and influence on surrounding tissues. We have generated a transgenic mouse that stably expressed a genetically encoded FRET-based fluorescent reporter for caspase activation and performed simultaneous time-lapse imaging of apoptosis and morphogenesis in living embryos. We found that inhibiting caspase activation perturbed and delayed the smooth progression of cranial NTC, suggesting that caspase-mediated cell removal facilitates NTC completion within a limited developmental window. In addition to NTC stages, apoptosis is also observed in various regions and stages during brain development. We are now investigating roles of apoptotic signaling in early brain formation after NTC as well as postnatal brain development.
Apoptotic cells are abundantly observed in the early developing brain. It was proposed that apoptosis-deficiency causes brain overgrowth, but we demonstrated that brain malformations in apoptosis-deficient mutants are due to insufficient brain ventricle expansion as a result of uncompleted cranial neural tube closure. Apoptosis eliminates Fgf8-expressing cells in the anterior neural ridge (ANR), which acts as an organizing center of the forebrain by producing FGF8 morphogen. Deficiency of apoptosis leads to the accumulation of non-proliferative undead cells in the ventral part of the ANR. The undead cells in apoptosis-deficient mutants express Fgf8 continuously, which perturbs gene expression in the ventral forebrain. From these observations, we proposed that apoptosis within a specific subdomain of the ANR is required for correct temporal elimination of FGF8-producing region within a limited developmental time window, thereby ensuring proper forebrain development.



References Nonomura, K., Yamaguchi, Y., Hamachi, M., Koike, M., Uchiyama, Y., Nakazato, K., Mochizuki, A., Sakaue-Sawano, A., Miyawaki, A., Yoshida, H., Kuida, K., and Miura, M.: Local apoptosis modulates early mammalian brain development through the elimination of morphogen producing cells. Dev. Cell 27, 621-634, 2013
Yamaguchi, Y., Shinotsuka, N., Nonomura, K., Takemoto, K., Kuida, K., Yoshida, H., and Miura, M.: Live imaging of apoptosis in a novel transgenic mouse highlights its role in neural tube closure.
J. Cell Biol. 195, 1047-1060, 2011

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