[Frontiers in Bioscience 2, d88-125, March 1, 1997]

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Bianca Marchetti

Department of Pharmacology, Medical School, University of Catania, 95125 Catania, Laboratory of Biotech. Neuropharmacology, OASI Institute for Research and Care (IRCCS) on Mental Retardation and Brain Aging (IRCCS) Troina, (EN), Italy.

Received 8/2/96; Accepted 2/20/97; On-line 3/1/97

17. Summary and Conclusion

All together, the presented information supports the concept that astroglia participate in CNS intercellular communication and in the interaction between the nervous and immune systems. In particular, this review has emphasized the commonality of signaling networks shared by LHRH neurons and glial cells. Glial cells play active roles from embryonic development to adulthood. During development, astroglia direct the migration of neurons to the right targets. In the adult brain and spinal cord, the oligodendrocytes in he CNS, and the Schwann cells in the peripheral nervous system, participate in propagation of electrical impulses. The microglia serves as the brain's immune cell. But as pointed out by John Travis (21), the real "stars" in this scenario are the astrocytes, able to manufacture a wide variety of signaling molecules, providing the metabolic support for neuronal function, and involved in memory and information processing. The LHRH neuronal system needs to "navigate" from the epithelium of the medial olfactory pit to the developing basal forebrain. The failure of glial-guided migration is responsible for the suppression of the pituitary-gonadal axis in Kallman's syndrome. Recent findings clearly indicate that besides its well known trophic role, astroglia may play a crucial regulatory function that may vary according to: 1. the specific physiological conditions (i.e.: stage of glia maturation and differentiation), 2. the specific brain region examined, 3. the degree of neuronal differentiation; and 4. the hormonal background. Such control may be exerted through the release of products able to alter LHRH neuronal morphology, the LHRH intracellular secretory machinery and/or proliferation. As a corollary, astroglial cells can respond to GT1-1 neuronal signals, and this mutual trophic and functional interaction is likely to occur via paracrine, and/or autocrine mechanism(s). Our preliminary observations would support the contention that glial-derived, peptide growth factors are involved in LHRH-astroglia crosstalk. On the other hand, other findings support the viewpoint that the hypothalamic decapeptide, LHRH, may act as a growth factor for astroglia. It would, then, appear that astroglia may produce different factors endowed with neurotrophic/differentiating properties, the nature and/or the concentration of which may vary according to the CNS region and the degree of astroglial differentiation. More importantly, glial-derived factors exert different effects according to the degree of GT1-1 neuron differentiation. The study on the role of cell-cell contacts and adhesive mechanisms between LHRH neurons and astroglia highlights the crucial importance of neuron/neuron, neuron/glia juxtaposition for the correct development of LHRH neuronal function in vitro. The dramatic effects on both morphology and secretory capacity of the LHRH neuron clearly indicate that the neural cell adhesion molecule is involved in the dynamic inter-signaling between LHRH neurons, as well as in neurons and astroglia. In view of the signal transduction capabilities of the extracellular matrix (260), a crosstalk between different signal pathways can provide a fine orchestration of cellular processes including growth, differentiation and secretory activity.

The fact that astroglial conditioned medium is able to stimulate the leukocyte proliferation is in line with the view of mutual regulatory mechanisms and shared molecules among neural, glial, endocrine and immune cells. This view is further supported during manipulation of astroglial-derived cytokines and NO induced lipopolysaccharide in LHRH-astroglial mixed cultures, underscoring a potential crosstalk between different mediators in the dynamic control of LHRH release.

LHRH immunoreactive neurons are seen to emerge from the olfactory placode by day 11.5, at 12 and 13 days of gestation cords of LHRH-immunoreactive cells are seen on the nasal septum, and by day 14 LHRH neurons enter the forebrain. Some data also indicate that glial cells arise in the olfactory epithelium and migrate into the olfactory nerve (261, 262). In the X-linked form of Kallmann's disease, the affected gene has recently been found to encode a protein that contains motifs common to several adhesion molecules (263, 264). Basic fibroblast growth factor stimulates both multipotential precursors, which give rise to neurons and astrocytes, and a committed glial precursor. Recently, FGF receptors have been implicated in cell-cell signaling and in cell migration (265-270). Growth factors in collaboration with molecule of the cell surface matrix may then cooperate during embryonic development for the migration and differentiation of the LHRH neuronal system, while in the adult brain they could participate in the neuroendocrine regulation of LHRH secretion. Detailed studies on different aspects of LHRH neuron-glia interactions seem warranted not only because of the clinical and genetic implications for patients with Kallmann's disorder, but might be of importance for the understanding of other migrating disorders.