Distinct modulatory actions of TGF-beta and LIF on neurotrophin-mediated survival of developing sensory neurons.
The neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) are important for the regulation of survival and differentiation of distinct, largely non-overlapping populations of embryonic sensory neurons. We show here that the multifunctional cytokine transforming growth factor-beta (TGF-beta) fails to maintain sensory neurons cultured from embryonic day (E) 8 chick dorsal root ganglia (DRG), although DRG neurons are immunoreactive for the TGF-beta receptor type II, which is essential for TGF-beta signaling. However, in combination with various concentrations of NT-3 and NT-4, but not NGF, TGF-beta 3 causes a further significant increase in neuron survival. In DRG cell cultures treated with NGF, NT-3, and NT-4, a neutralizing antibody to TGF-beta decreases neuron survival suggesting that endogenous TGF-beta in these cultures affects the efficacies of neurotrophins. Consistent with this notion and a modulatory role of TGF-beta in neurotrophin functions is the observation that TGF-beta 2 and -beta 3 immunoreactivities and TGF-beta 3 mRNA are located in embryonic chick DRG in close association with neurons from E5 onwards. We also show that leukemia inhibitory factor (LIF) significantly decreases NGF-mediated DRG neuron survival. Together, these data indicate that actions and efficacies of neurotrophins are under distinct control by TGF-beta and LIF in vitro, and possibly also in vivo.
Krieglstein
K
K
Department of Anatomy and Cell Biology, University of Heidelberg, Germany.
Unsicker
K
K
D000818:Animals; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D002642:Chick Embryo; D005727:Ganglia, Spinal / Q000737:chemistry / Q000166:cytology / Q000196:embryology; D006131:Growth Inhibitors / Q000494:pharmacology; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009475:Neurons, Afferent / Q000737:chemistry / Q000502:physiology*; D020933:Neurotrophin 3; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000494:pharmacology* / Q000502:physiology
D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D016212:Transforming Growth Factor beta; C073922:neurotrophin 4