Growth arrest failure, G1 restriction point override, and S phase death of sensory precursor cells in the absence of neurotrophin-3.
More than half of the dorsal root ganglion (DRG) neurons are lost by excessive cell death coinciding with precursor proliferation and cell cycle exit in neurotrophin-3 null mutant (NT-3-/-) mice. We find that in the absence of NT-3, sensory precursor cells fail to arrest the cell cycle, override the G1 phase restriction point, and die by apoptosis in S phase, which can be prevented in vivo by a cell cycle blocker. Uncoordinated cell cycle reentry is preceded by a failure of nuclear N-myc downregulation and is paralleled by the activation of the full repertoire of G1 and S phase cell cycle proteins required for cell cycle entry. Our results provide evidence for novel activity of neurotrophins in cell cycle control and point toward an N-myc sensitization to cell death in the nervous system that is under the control of NT-3.
ElShamy
W M
WM
Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
Fridvall
L K
LK
Ernfors
P
P
D000818:Animals; D002455:Cell Division / Q000235:genetics; D016193:G1 Phase / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000172:deficiency* / Q000235:genetics*; D009475:Neurons, Afferent / Q000473:pathology*; D020933:Neurotrophin 3; D016196:S Phase / Q000235:genetics*; D013234:Stem Cells / Q000473:pathology*
D009414:Nerve Growth Factors; D020933:Neurotrophin 3