Mutations affecting neural survival in the zebrafish Danio rerio.
Programmed cell death is a prominent feature of normal animal development. During neurogenesis, naturally occurring cell death is a mechanism to eliminate neurons that fail to make appropriate connections. To prevent accidental cell death, mechanisms that trigger programmed cell death, as well as the genetic components of the cell death program, are tightly controlled. In a large-scale mutagenesis screen for embryonic lethal mutations in zebrafish Danio rerio we have found 481 mutations with a neural degeneration phenotype. Here, we present 50 mutations that fall into two classes (termed spacehead and fala-like) that are characterized by two main features: first, they appear to affect cell survival primarily within the neuroectodermal lineages during somitogenesis, and second, they show an altered brain morphology at or before 28 hours of development. Evidence for the specificity of cell death within the central nervous system comes from visual inspection of dying cells and analysis of DNA fragmentation, a process associated with apoptotic cell death. In mutants, the level of dying cells is significantly increased in brain and spinal cord. Furthermore, at the end of somitogenesis, the cell count of radial glia and trigeminal neurons is reduced in some mutants of the spacehead class. A variety of neurodegenerative 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 disorders within the CNS and the activation of inappropriate programmed cell death.
Abdelilah
S
S
Massachusetts General Hospital, Harvard Medical School, Charlestown 02129, USA.
Mountcastle-Shah
E
E
Harvey
M
M
Solnica-Krezel
L
L
Schier
A F
AF
Stemple
D L
DL
Malicki
J
J
Neuhauss
S C
SC
Zwartkruis
F
F
Stainier
D Y
DY
Rangini
Z
Z
Driever
W
W
D000818:Animals; D019521:Body Patterning / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D005816:Genetic Complementation Test; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics; D009474:Neurons / Q000502:physiology*; D010641:Phenotype; D012249:Rhombencephalon / Q000196:embryology; D015027:Zebrafish / Q000196:embryology / Q000235:genetics*