Programmed Cell Death in Mouse Brain Development

Abstract

Among the basic cellular events that shape the developing brain, programmed cell death (also called apoptosis) plays an essential role (Cowan et al. 1984; Oppenheim 1991). Although cell death during the development of the vertebrate nervous system was first described by anatomists of the nineteenth century, a mechanistic understanding of these events started only in the latter half of this century through two lines of research. First, the identification of nerve growth factor (NGF) by R. Levi-Montalcini and colleagues showed that cells died if deprived of trophic molecules and thus established the foundation for the “trophic theory” of neural development. Second, H. R. Horvitz pioneered genetic studies of programmed cell death in the nematode Caenorhabditis elegans and elucidated a genetic pathway involved in this process. Because the targeted disruption of specific genes in the mouse can now be performed, we can test directly whether the same cell death machinery is conserved in mammals. Moreover, the similarity of the organization and development of the central nervous system between the mouse and higher primates makes it an ideal experimental system for understanding the roles of programmed cell death in normal human brain development and congenital malformations. The present chapter focuses on the recent gene targeting studies elucidating the evolutionarily conserved cell death machinery in the context of mouse brain development.