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Cross-Talk Between Neurons and Glia: Highlights on Soluble Factors

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Cross-Talk Between Neurons and Glia: Highlights on Soluble Factors Neuron-gliaBrazilian Journal interactions of Medical during and nervous Biological system Research development (2001) 34: 611-620 611 ISSN 0100-879X Review Cross-talk between neurons and glia: highlights on soluble factors F.C.A. Gomes, Instituto de Ciências Biomédicas, Departamento de Anatomia, T.C.L.S. Spohr, R. Martinez Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil and V. Moura Neto Abstract Correspondence The development of the nervous system is guided by a balanced action Key words F.C.A. Gomes between intrinsic factors represented by the genetic program and · Neuron-glia interaction Departamento de Anatomia epigenetic factors characterized by cell-cell interactions which neural · Trophic factors ICB, UFRJ, CCS, Bloco F · cells might perform throughout nervous system morphogenesis. Highly Astrocyte 21949-590 Rio de Janeiro, RJ · Neuron relevant among them are neuron-glia interactions. Several soluble Brasil · Nervous system Fax: +55-21-562-6493 factors secreted by either glial or neuronal cells have been implicated E-mail: [email protected] in the mutual influence these cells exert on each other. In this review, we will focus our attention on recent advances in the understanding of Presented at the role of glial and neuronal trophic factors in nervous system SIMEC 2000 - International development. We will argue that the functional architecture of the Symposium on Extracellular Matrix, Angra dos Reis, RJ, brain depends on an intimate neuron-glia partnership. Brazil, September 24-27, 2000. Research supported by PRONEX-MCT (No. 052/97), CAPES-COFECUB, Introduction Neuron-glia interactions control several FAPERJ, FINEP, and CEPG-UFRJ. processes of brain development such as neu- A central objective of developmental bi- rogenesis (1), myelination (2), synapse for- ology is to elucidate the mechanisms that mation (3), neuronal migration (4), prolif- Received October 31, 2000 specify particular cell types during animal eration (5) and differentiation (6) and even Accepted February 20, 2001 development. The central nervous system neuronal signaling (7,8). Several soluble fac- (CNS) provides an interesting model to iden- tors secreted by either glial or neuronal cells, tify the development programs that create such as neurotransmitters, hormones and cell type-specific patterns. Within this con- growth factors, have been implicated in ner- text, cell-cell interactions are of fundamental vous system morphogenesis. Although glia- importance in the organization and mainte- glia interactions greatly contribute to this nance of the nervous system architecture. process it is not the scope of the present For a long time glial cells were regarded as report to discuss their implications. In this somewhat passive companions to neurons review, we will focus our attention on recent that performed a variety of essential but al- advances in the understanding of the role of most perfunctory duties. Today, however, glial and neuronal trophic factors in nervous more than a century after their description by system development. Taken together with Virchow, increasing evidence has been ac- data about cell molecule contact described cumulating indicating that neurons and glial elsewhere, the present report contributes to cells have an intimate and plastic morpho- the discussion of mechanisms involved in logical and functional relationship. neuron-glia interactions. Braz J Med Biol Res 34(5) 2001 612 F.C.A. Gomes et al. Soluble factors as neuron-glia (11). Knockout animals for the bcl2 gene, a interaction mediators modulator of apoptosis, in addition to the death of a large amount of retina ganglion Neuron-glia interactions: implications in the cells (RGC), present increased oligodendro- matching of axons/oligodendrocytes and cyte death, emphasizing the role of neuronal Schwann cell number factors in sustaining oligodendrocyte sur- vival and/or proliferation (2). Additionally, Most of our knowledge concerning neu- neurons and neuronal extracts are known to ron-glia interactions concerns the effects of provide a mitogenic signal for both imma- glial cells on neuronal morphogenesis. How- ture and mature oligodendrocytes (12,13). ever, evidence has accumulated in the past years pointing to a mutual influence between The role of neuregulin these two cell types. Most data about the action of neuronal Several candidate mitogens and survival factors on glial cells concern neuron-oligo- factors have been identified that are effec- dendrocyte interactions. Nearly ten years ago, tive at different stages in the oligodendro- glia-promoting factors (GPF), brain peptides cyte lineage: platelet-derived growth factor which stimulate growth of specific macro- (PDGF) (14), basic fibroblast growth factor glial populations in vitro, were identified (bFGF), neurotrophin-3 and insulin growth (9). First discovered in the goldfish visual factor (2). All of these factors are released by system, peptides with similar properties were astrocytes and bFGF and PDGF are expressed later identified in the mammalian brain. Some and released by neurons as well. Recently, of them, GPF1 and GPF3, are secreted by members of the bone morphogenetic protein neurons and represent a source of oligoden- family have been shown to inhibit oligoden- droglia-stimulating factors (9). At present, it drocyte differentiation in vitro (15). The most is widely recognized that the survival and promising candidate for the neuronal control proliferation of oligodendrocytes are highly of oligodendrocyte progenitor proliferation dependent on neuronal contact and neuronal is glial growth factor 2 (GGF2) from the soluble factors (2). Soluble factors secreted neuregulin family (16). The NDF/neuregulin by axons apparently control oligodendro- family includes more than a dozen growth genesis by stimulating oligodendrocyte pre- and differentiation factors that share an epi- cursor proliferation. Once cell division has dermal growth factor (EGF)-like motif, serv- ceased the cells must meet a nonmyelinized ing as the receptor-binding domain. GGF2 axon in order to survive. Such refinement of has been reported as a potent mitogen and oligodendrocyte-neuron interaction plays a survival factor for the oligodendrocyte lin- crucial role in matching the number of oligo- eage and its progenitors and as an inhibitor dendrocytes and myelinized axons, thus en- of pro-oligodendrocyte differentiation. Sev- suring that the number of free axons does not eral studies have shown that oligodendro- exceed that of oligodendrocytes. Transec- cyte proliferation is under the control of tion of the optic nerve during development several mitogens that operate at different results in a severe reduction in the number of stages in the oligodendrocyte lineage. While oligodendrocytes, suggesting a dependence GGF and PDGF are likely to regulate early of developing oligodendroglia on neuronal progenitors, GGF and FGF may function at survival factors (10). Furthermore, transec- later times on more differentiated cells (16). tion of the adult optic nerve results in a A similar neuronal control of cell prolif- substantial reduction in the expression of the eration and differentiation has been reported myelin-related gene by oligodendrocytes for Schwann cells, involved in peripheral Braz J Med Biol Res 34(5) 2001 Neuron-glia interactions during nervous system development 613 nervous system myelinization (17). GGF is a dendrocyte precursor cells grown in primary strong mitogenic molecule for Schwann cells, culture that non-NMDA glutamate receptor secreted by neural precursors of peripheral agonists inhibit cell proliferation. Recently, ganglia (17,18). Members of the neuregulin these investigators showed that in cerebellar family reduce the apoptosis of mature slice cultures glutamate acts as an antimi- Schwann cells upon axotomy (15), probably totic signal at all proliferative stages in the reflecting a role in attaining the appropriate oligodendrocyte lineage. Treatment of cer- ratio of neurons to Schwann cells in adults ebellar slices with kainate or AMPA caused (19). The severe deficiency of Schwann cells a 55 and 37% decrease, respectively, in the in mice in which the neuregulin-1 gene has mRNA levels of the oligodendrocyte matu- been inactivated provides striking support ration marker CNPase (23 cyclic nucleo- for the key role of this growth factor in tide 3 phosphodiesterase). In contrast, treat- Schwann cell development (20). Further- ment with the glutamate receptor antagonist more, GGF2 is also involved in glial fate significantly increased CNPase RNA levels determination. This factor causes neural crest by 32% (24). stem cells to acquire a glial phenotype in- In addition to PDGF, GGF, bFGF and stead of a neuronal fate (21). Indeed, GGF2 others, glutamate and its receptors are likely mutants lack Schwann cell precursors along to be part of the complex network of signals peripheral projections from the spinal cord that regulate oligodendrocyte development (20). in vivo. Understanding the cues provided by Although axons are required for oligo- neuronal cells to oligodendrocytes and dendrocyte differentiation and myelination, Schwann cells might open new perspectives tissue culture studies suggest that initially in elucidating myelination and regeneration they promote proliferation and delay myeli- in the CNS as well as in the peripheral nation of oligodendrocyte progenitors, pos- nervous system. sibly by secreting GGF (for a review, see 2). Similar effects on Schwann cell myelination Neuron-microglia interactions:
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