Macrophage-derived tumor necrosis factor alpha, an early developmental signal for motoneuron death.
Mechanisms inducing neuronal death at defined times during embryogenesis remain enigmatic. We show in explants that a developmental switch occurs between embryonic day 12 (E12) and E13 in rats that is 72-48 hr before programmed cell death. Half the motoneurons isolated from peripheral tissues at E12 escape programmed cell death, whereas 90% of motoneurons isolated at E13 enter a death program. The surrounding somite commits E12 motoneurons to death. This effect requires macrophage cells, is mimicked by tumor necrosis factor alpha (TNFalpha), and is inhibited by anti-TNFalpha antibodies. In vivo, TNFalpha is detected within somite macrophages, and TNF receptor 1 (TNFR1) is detected within motoneurons precisely between E12 and E13. Although motoneuron cell death occurs normally in TNFalpha-/- mice, this process is significantly reduced in explants from TNFalpha-/- and TNFR1-/- mice. Thus, embryonic motoneurons acquire the competence to die, before the onset of programmed cell death, from extrinsic signals such as macrophage-derived TNFalpha
Sedel
Frédéric
F
Laboratoire de Biologie Cellulaire de la Synapse Normale et Pathologique, Institut National de la Santé et de la Recherche Médicale Unité 497, Ecole Normale Supérieure, 75005 Paris, France.
Béchade
Catherine
C
Vyas
Sheela
S
Triller
Antoine
A
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D047888:Receptors, Tumor Necrosis Factor, Type I; D019170:Somites / Q000166:cytology / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D015703:Antigens, CD; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha