TNFα contributes to the death of NGF-dependent neurons during development

Abstract

Many sympathetic and sensory neurons depend on a supply of nerve growth factor (NGF) from their targets during development, and neurons that fail to obtain sufficient NGF die by apoptosis. Here we show that tumor necrosis factor alpha (TNFalpha) is involved in bringing about the death of NGF-deprived neurons. Function-blocking antibodies against either TNFalpha or TNF receptor 1 (TNFR1) rescued many sympathetic and sensory neurons following NGF deprivation in vitro. Fewer sympathetic and sensory neurons died during the phase of naturally occurring neuronal death in TNF-deficient embryos, and neurons from these embryos survived in culture better than wild-type neurons. These neurons coexpress TNFalpha and TNFR1 during this stage of development, suggesting that TNFalpha acts by an autocrine loop.

Tumor Necrosis Factor α Regulates Responses to Nerve Growth Factor, Promoting Neural Cell Survival but Suppressing Differentiation of Neuroblastoma Cells

“…Several groups have independently reported the synthesis of TNF-␣ in neural cells, including multipotential neural stem cells and differentiated hippocampal neurons (Barker et al, 2001;Sarkar and Sharma, 2002;Renauld and Spengler, 2002;Klassen et al, 2003). Endogenous TNF-␣ in NGF-dependent neurons is reported to contribute to induction of neural cell death through TNFR1 after withdrawal of NGF (Barker et al, 2001).…”

“…Endogenous TNF-␣ in NGF-dependent neurons is reported to contribute to induction of neural cell death through TNFR1 after withdrawal of NGF (Barker et al, 2001). However, TNF-␣ is expressed not only in dying neurons but also in surviving neurons (Barker et al, 2001) and the function of endogenous TNF-␣ in surviving neurons has not been clarified.…”

“…Endogenous TNF-␣ in NGF-dependent neurons is reported to contribute to induction of neural cell death through TNFR1 after withdrawal of NGF (Barker et al, 2001). However, TNF-␣ is expressed not only in dying neurons but also in surviving neurons (Barker et al, 2001) and the function of endogenous TNF-␣ in surviving neurons has not been clarified. Other groups have reported endogenous TNF-␣ in other types of neurons, but could not show significant death of neurons that express TNF-␣ (Renauld and Spengler, 2002;Sarkar and Sharma, 2002;Klassen et al, 2003).…”

“…In addition to the NGF-dependent survival of neurons, activation of Akt is associated with TNFR2-mediated survival of neurons (Fontaine et al, 2002;Marchetti et al, 2004). These results indicate that TNF-␣ could contribute to survival of neurons through TNFR2 at least under some conditions, although TNF-␣ shows cytotoxic effects on neurons through TNFR1 in the absence of NGF (Barker et al, 2001). Effects of endogenous TNF-␣ on neurons in the presence of NGF are still unknown.…”

“…Tumor necrosis factor ␣ (TNF-␣) is a cytokine that contributes to this neural cell death (Barker et al, 2001). Barker et al (2001) show that TNF-␣ is expressed in neurons that depend upon NGF for their survival. The endogenous TNF-␣ does not kill neurons in the presence of NGF.…”