Experimental autoimmune model of nerve growth factor deprivation: Effects on developing peripheral sympathetic and sensory neurons

Abstract

An experimental autoimmune model of nerve growth factor (NGF) deprivation has been used to assess the role of NGF in the development of various cell types in the nervous system. Adult rats immunized with 2.5S mouse NGF in complete Freund's adjuvant produced antibodies that crossreacted with their own NGF and that were transferred in utero to the fetus and in milk to the neonate. Cross-fostering experiments were carried out to separate the effects of exposure to anti-NGF in utero from those due to exposure through the milk. Anti-NGF transferred in utero and in milk resulted in the destruction of peripheral sympathetic neurons assessed by morphological methods (light microscopy) and biochemical methods (tyrosine hydroxylase activity, choline acetyltransferase activity, and protein content). No effects were observed on the adrenal medulla. Offspring of NGF-immunized females exposed to anti-NGF in utero had a decreased protein content in the dorsal root ganglia and were unable to transport 125I-labeled NGF injected in the forepaw to the dorsal root ganglia. These results suggest that a subpopulation of sensory neurons is dependent on NGF for survival during some period of fetal development. This model offers the potential for determining the degree and time of dependence of various cell types on NGF. Nerve growth factor (NGF) is a protein that acts on peripheral neurons of neural crest origin in both avian and mammalian species (1). Much evidence suggests that NGF is a retrogradely transported trophic factor that regulates the development of immature sympathetic peripheral neurons and the maintenance of mature sympathetic neurons (2-4). Very little is known about the role of NGF for mammalian sensory neurons, although it has been shown that rat dorsal root ganglion (DRG) neurons retain the capability of retrograde axonal transport of NGF throughout postnatal development (5).One means of assessing the physiological role of NGF on the diverse neuronal populations of the developing mammalian nervous system is to deprive cells of NGF. Because the normal source of NGF is not known, and specific NGF antagonists are not available, the only mechanism of producing a systemic deprivation of NGF is immunological. Previous studies (6)(7)(8) have demonstrated that antibodies to NGF can be prepared by repeated injections of animals with NGF derived from mouse. These and subsequent studies, using anti-NGF serum, demonstrated that mammalian sympathetic neurons of the paraand prevertebral ganglia die if deprived of NGF during the neonatal period. Other neural cell types (the short adrenergic neurons innervating the urogenital tract and brown adipose tissue, adrenal medullary chromaffin cells, peripheral sensory neurons of the DRG, and central adrenergic neurons) are not destroyed by anti-NGF serum administered in the neonatal period (9, 10).The usefulness of antiserum-induced NGF deprivation is limited by problems associated with its repeated administration-e.g., serum sickness. An an alternative approach, we have developed ...

BDNF activated TrkB/IRR receptor chimera promotes survival of sympathetic neurons through Ras and PI‐3 kinase signaling

“…Sympathetic neurons of the superior cervical ganglion (SCG) derived from postnatal day (P)0 to P3 neonate pups require neurotrophic support for appropriate survival and differentiation both in vitro and in vivo (LeviMontalcini and Booker, 1960;Gorin and Johnson, 1979;Vogel et al, 1995;Martin et al, 1998;Vogel and Parada, 1998). Since the activated TrkB/IRR chimeric receptor can mimic TrkA differentiation in PC12 cells, we investigated whether the TrkB/IRR receptor confers a similar response in cultured primary sympathetic neurons.…”

Mouse nerve growth factor gene: structure and expression.

“…Of these cells, a significant proportion dies in the first few weeks after birth (approximately 30% for the sympathetic neurons in the rat superior cervical ganglion). Injection of antibodies to NGF during the development of sympathetic and sensory neurons results in the death of these cells (9,18). Administration of purified NGF permits the survival of all these cells, including those that would normally die (1).…”

Evidence that endogenous beta nerve growth factor is responsible for the collateral sprouting, but not the regeneration, of nociceptive axons in adult rats.

“…Although /3 nerve growth factor (NGF) is essential for the development and survival of neuronal populations in the autonomic and sensory nervous systems (1)(2)(3)(4), by birth or shortly thereafter, sensory neurons will survive largely independent of it (1,5). Nevertheless in adult animals NGF continues to be synthesized in peripheral target tissues (6,7), sensory axons can take up and transport it retrogradely (8,9), while maintained NGF deprivation leads to a lowering ofboth substance P levels (10), and even neuronal cell size (11), in dorsal root ganglia.…”