Aggressive behavior induces release of nerve growth factor from mouse salivary gland into the bloodstream.

Aloe, Luigi; Alleva, Enrico; Bohm, Ariela; Levi‐Montalcini, Rita

doi:10.1073/pnas.83.16.6184

Cited by 209 publications

(88 citation statements)

References 26 publications

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“…This may be due to the much higher number of fighting episodes that occurs as a result of isolation. Fighting induced a large increase in biologically active NGF in serum from isolated mice, when compared with the isolated nonfighting group, in agreement with previous results (22). The neurite outgrowth induced by both serum and hypothalamic extracts from chicken dorsal root ganglia and rat SCG was completely inhibited by NGF antibodies.…”

Section: Resultssupporting

confidence: 81%

“…' , ._ P-< DISCUSSION Previous studies (22) showed that intraspecific fighting induced by social isolation results in a massive release of biologically active NGF from the submaxillary gland of adult male mice into the bloodstream and that the amount of circulating NGF is highly correlated with the number of fighting episodes. In this report we show that the same experimental paradigm leads also to a marked increase in NGF mRNA in the hypothalamus.…”

Section: Resultsmentioning

confidence: 97%

“…Aloe et al (22) showed that intermale aggressive behavior in mice induced by social isolation leads to a marked release of biologically active NGF from the submaxillary salivary gland into the bloodstream. We now report that the same behavioral paradigm leads to a large and specific increase in NGF mRNA and protein in the hypothalamus, where NGF mRNA was found in nerve cells by in situ hybridization.…”

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confidence: 99%

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Nerve growth factor mRNA and protein increase in hypothalamus in a mouse model of aggression.

Spillantini

Aloe²,

Alleva³

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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113

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The effects of intermale aggressive behavior induced by social isolation on the level of nerve growth factor (NGF) mRNA and protein were investigated in central and peripheral mouse tissues. A large increase in NGF mRNA and protein was observed in hypothalamus, with no changes in cerebral cortex, hippocampus, and cerebellum. No change in NGF mRNA levels was found in heart, spleen, vas deferens, and submaxillary salivary gland. The cellular localization of NGF mRNA in the central nervous system was investigated by in situ hybridization. Numerous nerve cells were specifically labeled in preoptic and ventrolateral nuclei of the hypothalamus, as well as in the cornu ammonis region of the hippocampus and throughout all layers of the cerebral cortex, with the highest concentration in layer III. The present results firmly establish that nerve cells constitute the major source of NGF in the brain. They also open the way to understanding the regulation of NGF biosynthesis in the central nervous system. Nerve growth factor (NGF) is a protein required for the development and maintenance of sympathetic neurons and the majority of neural crest-derived sensory nerve cells (1). It functions as a retrograde trophic messenger between target tissues and their innervating nerve cells. Accordingly, NGF mRNA has been detected in peripheral tissues of various mammalian species (2, 3), whereas NGF receptor mRNA is mostly produced by the corresponding sensory and sympathetic ganglia (4). The actions of NGF are not limited to the peripheral nervous system. Both NGF and its receptor are produced throughout the central nervous system of various mammalian species (4-13) and NGF is retrogradely axonally transported from neocortex and hippocampus to basal forebrain magnocellular cholinergic nerve cells (14,15), where it exerts trophic actions (16-18). Moreover, the degeneration of basal forebrain neurons observed following transection of the septohippocampal pathway is markedly reduced by NGF (19-21). These results suggest that NGF may function as a retrograde trophic messenger for basal forebrain cholinergic nerve cells. However, the widespread occurrence of NGF mRNA throughout the central nervous system suggests additional functions.Whereas a great deal of information is available about the sites of synthesis of NGF in the central nervous system and about some of its biological actions, relatively little is known about the factors regulating NGF synthesis. Aloe et al. (22) showed that intermale aggressive behavior in mice induced by social isolation leads to a marked release of biologically active NGF from the submaxillary salivary gland into the bloodstream. We now report that the same behavioral paradigm leads to a large and specific increase in NGF mRNA and protein in the hypothalamus, where NGF mRNA was found in nerve cells by in situ hybridization. Part of this work has been presented in abstract form. § MATERIALS AND METHODS Behavioral Studies. Male mice of a Swiss-derived (CD-1) strain, with previous breeding experience, w...

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Section: Resultssupporting

confidence: 81%

Section: Resultsmentioning

confidence: 97%

mentioning

confidence: 99%

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Nerve growth factor mRNA and protein increase in hypothalamus in a mouse model of aggression.

Spillantini

Aloe²,

Alleva³

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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113

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“…Aggressive behavior in male mice results in the release into the blood of large amounts of submaxillary NGF and renin (4,5), providing some evidence that these molecules play a physiological role. But surprisingly, these proteins are not detected in the SMG of related species.…”

Section: Introductionmentioning

confidence: 99%

High level of accumulation of a mRNA coding for a precursor-like protein in the submaxillary gland of male rats.

Rosinski‐Chupin

Tronik

Rougeon

1988

Proc. Natl. Acad. Sci. U.S.A.

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NaDodSO4/PAGE analysis of in vitro translation products of rat submaxillary gland (SMG) mRNAs has revealed an important sexual dimorphism. Moreover, most of the rat male-specific major translation products differ in size from those translated from male mouse SMG mRNAs. To characterize proteins accumulated in the rat SMG under androgen control, a cDNA library was constructed. Here we report the nucleotide sequence of a 0.7-kilobase mRNA that is 1000-3000 times more abundant in male rats than in female rats. The predicted corresponding protein, SMR1, has a molecular weight of 16,000 and contains a signal peptide for secretion and potential signals for glycosylation. An interesting feature of SMR1 is the presence, in a hydrophilic region, of the tetrapeptide Gln-His-Asn-Pro surrounded by two pairs of basic residues that represent potential cleavage sites for maturation enzymes. In rats, the tissue distribution of the SMR1 mRNA is restricted to the SMG and the prostate. Only very low amounts of SMR1 mRNA can be detected in the SMG of male or female mice. Southern blot analysis indicates the presence of three genes in rats but only one in mice. Hypotheses on the physiological role of SMR1-derived peptides in male rats are discussed.A large number of polypeptides with biologically defined properties are synthesized at high levels in the submaxillary gland (SMG) of rodents (1) and particularly of mice. These proteins, including nerve growth factor (NGF), epidermal growth factor (EGF), and renin, share a number of properties. All are synthesized in the same cell type-the granular convoluted tubular (GCT) cells-in response to various hormonal stimuli, in particular to androgens (2). Further, these secretory proteins can be found in the saliva of mice and are synthesized as precursors that become active after posttranslational processing events, possibly involving kallikrein-like proteinases. Some of these kallikrein-like proteinases are also synthesized under androgen-control in the SMG (3).The biological significance of the accumulation of these polypeptides in the SMG of mice and of their release into the saliva is still unclear. Aggressive behavior in male mice results in the release into the blood of large amounts of submaxillary NGF and renin (4,5), providing some evidence that these molecules play a physiological role. But surprisingly, these proteins are not detected in the SMG of related species. For instance, renin, which represents 2% of the SMG proteins in wild-type and most inbred male mice (6) is not found in the SMG of rats (7). This suggests that these SMG-synthesized polypeptides could be related to the especially aggressive behavior of male mice.Attempts to characterize the genes regulated by androgens in the SMG of rats led us to analyze the patterns of in vitro translation products directed by the mRNAs of this tissue. As in mice, an important sexual dimorphism was observed in the rat SMG translation products. Moreover, the major polypeptides accumulated in the two species appeared to be very ...

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“…9 -10). NGF accelerates the rate of wound healing in mice (11) and is released into the bloodstream of male mice from the salivary gland after fighting (12).…”

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confidence: 99%

Nerve Growth Factor Induces the Expression of Certain Cytokine Genes and bcl-2 in Mast Cells

Bullock

Johnson

1996

Journal of Biological Chemistry

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Nerve growth factor (NGF) promotes mast cell survival in vitro (Horigome, K., Bullock, E. D., and Johnson, E. M., Jr. (1994) J. Biol. Chem. 269, 2695-2702). NGF survival promotion is cell density-dependent, and conditioned medium experiments have shown that NGF increases the production of an autocrine mast cell survival activity. Cytokines are potential candidates for autocrine survival factors. In rat peritoneal mast cells (RPMC), NGF caused an increase in the messenger RNAs for interleukin (IL)-3, IL-4, IL-10, tumor necrosis factor-␣, and granulocyte-macrophage colony-stimulating factor. This induction was NGF dose-dependent, was blocked by NGF-neutralizing antibodies, and was not observed in the non-mast peritoneal cell population. The immunosuppressive agent, cyclosporin A, blocked both cytokine induction and NGF-activated survival promotion but not survival promotion activated by IL-3 or stem cell factor, suggesting that NGF enhanced RPMC survival by increasing cytokine production. We also examine the effects of NGF on the expression levels of some members of the bcl-2 family and the interleukin-1␤-converting enzyme-like cysteine protease families. NGF markedly increased bcl-2 expression but had little or no effect on the other genes studied. The induction of bcl-2 mRNA by NGF was not blocked by cyclosporin A. These data suggest that induced cytokine gene expression but not increased expression of bcl-2 mediates NGFsurvival promotion in RPMC.

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Aggressive behavior induces release of nerve growth factor from mouse salivary gland into the bloodstream.

Cited by 209 publications

References 26 publications

Nerve growth factor mRNA and protein increase in hypothalamus in a mouse model of aggression.

Nerve growth factor mRNA and protein increase in hypothalamus in a mouse model of aggression.

High level of accumulation of a mRNA coding for a precursor-like protein in the submaxillary gland of male rats.

Nerve Growth Factor Induces the Expression of Certain Cytokine Genes and bcl-2 in Mast Cells

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