MUTATIONS AFFECTING NEURAL SURVIVAL IN THE ZEBRAFISH DANIO-RERIO

Programmed cell death is a prominent feature of normal animal developm ent, During neurogenesis, naturally occurring cell death is a mechanis m to eliminate neurons that fail to make appropriate connections, To p revent accidental cell death, mechanisms that trigger programmed cell death, as well as the genetic components of the cell death program, ar e tightly controlled. In a large-scale mutagenesis screen for embryoni c lethal mutations in zebrafish Danio rerio we have found 481 mutation s with a neural degeneration phenotype, Here, we present 50 mutations that fall into two classes (termed spacehead and fala-like) that are c haracterized by two main features: first, they appear to affect cell s urvival primarily within the neuroectodermal lineages during somitogen esis, and second, they show an altered brain morphology at or before 2 8 hours of development, Evidence for the specificity of cell death wit hin the central nervous system comes from visual inspection of dying c ells and analysis of DNA fragmentation, a process associated with apop totic cell death. In mutants, the level of dying cells is significantl y increased in brain and spinal cord, Furthermore, at the end of somit ogenesis, the cell count of radial glia and trigeminal neurons is redu ced in some mutants of the spacehead class. A variety of neurodegenera tive disorders in mouse and humans have been associated with abnormal levels of programmed cell death within the central nervous system, The mutations presented here might provide a genetic framework to aid in the understanding of the etiology of degenerative and physiological di sorders within the CNS and the activation of inappropriate programmed cell death.