sign in sign up
<<
Home , Schwann cell

BrazilianNeuron- Journal interactions of Medical during and nervous Biological system Research development (2001) 34: 611-620 611 ISSN 0100-879X Review

Cross-talk between 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 is guided by a balanced action Key words F.C.A. Gomes between intrinsic factors represented by the genetic program and · -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 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), 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 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 Neuron-glia interactions: implications in the cells (RGC), present increased oligodendro- matching of / and cyte death, emphasizing the role of neuronal Schwann cell number factors in sustaining 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 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), -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 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 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 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 results in a A similar neuronal control of cell prolif- substantial reduction in the expression of the eration and differentiation has been reported -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 (2’3’ 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 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- interactions: the basis of have been reported, indicating that high lev- nervous system inflammatory response els of neuronal mitogens can promote prolif- eration and arrest myelination in both the Neuron-derived growth factors have been CNS and the peripheral nervous system. By implicated in the modulation of nervous sys- promoting the survival and proliferation of tem inflammatory response. In the develop- both immature oligodendrocytes and Schwann ing CNS, invading monocytes proliferate and cells, may therefore play a cru- are transformed into ameboid microglia, an cial role during development in adjusting the atypical subclass of glial cells, also called final number of myelinating glial cells to the brain macrophages (25). Proliferation of number of available axons. microglia can be stimulated by colony-stimu- lating factors (CSF), such as CSF-1, also The role of neurotransmitters called macrophage CSF and granulocyte macrophage CSF. Recently, Dobbertin et al. In addition to traditional growth factors, (26) demonstrated that rat neurons stimulate recognition of the role of nonconventional macrophage proliferation by increasing their trophic factors such as neurotransmitters has mitogenic response to CSF. This effect was been growing for the last ten years. Most of shown to be mediated by secretion of trans- them might regulate neurogenesis as well as forming growth factor ß2 (TGF-ß2), a mem- gliogenesis (22). Gallo et al. (23) have dem- ber of the TGF-ß superfamily which is com- onstrated by using purified cortical oligo- posed of a range of functional and structural

Braz J Med Biol Res 34(5) 2001 614 F.C.A. Gomes et al.

factor subclasses with a range of cellular vival (30). actions and developmental regulatory effects For a long time it has been suspected that on organogenesis, pattern formation, modu- astrocytic cells play a trophic role in sup- lation of extracellular matrix and terminal porting neurons (31). Factors of the FGF, differentiation (27). All those data provided TGF and EGF families play an important evidence that neurons might support micro- role in early neurogenesis (32,33) and all of glia growth during development by secreting them are potentially secreted by astrocytes. TGF-ß2, which stimulates the proliferation Members of the EGF and FGF families are of brain macrophages and their precursors potent mitogens for multipotential neural infiltrating CNS tissue. progenitors and are highly implicated in sev- Recently, a new loop in neuron-micro- eral aspects of neurogenesis (22). Members glia interaction has emerged. Noda et al. (28) of the TGF-ß family such as TGF-ß itself and have identified functional subtypes of gluta- glial cell line-derived neurotrophic factor mate receptors in rat cerebral microglia. Al- have been reported to have a broad spectrum though the physiological role of these recep- of action during nervous system develop- tors in microglia remains unclear the authors ment. Both are known to favor survival of reported that their activation enhances tu- dopaminergic neurons in vivo as well as in mor necrosis factor alpha (TNF-a) produc- vitro (34,35). We have recently reported that tion by microglia. Since TNF-a rapidly in- TNF-ß and EGF secreted by cultured cer- creases after excitotoxic, ischemic and trau- ebellar astrocytes in response to thyroid hor- matic brain injury, it is possible that elevated mone (T3) treatment can modulate neuronal levels of glutamate at pathological sites may proliferation (5). Cerebellar neurons main- directly activate receptors on microglia, in- tained in the presence of conditioned medi- ducing a prompt response to injury. Another um derived from T3-treated astrocytes pre- putative mediator of neuron-microglia sig- sented a three-fold increase in the incorpora- naling is platelet-activating factor (PAF) tion of the proliferation marker, bromode- which is a potent phospholipid mediator that oxyuridyl. Neuronal survival was not af- plays several roles in neuronal function and fected by GGF, suggesting a prior function brain development. Aihara et al. (29) dem- for TNF-ß and EGF in glia-mediated neu- onstrated that cultivated neurons synthesized ronal proliferation. Additionally, Trentin A, PAF following stimulation with glutamic Alvarez M and Moura Neto V (unpublished acid. Microglia, which express functional results) identified several other growth fac- PAF receptors, showed a marked chemotac- tors secreted by astrocytes in response to T3 tic response to this factor, pointing to PAF as such as aFGF and bFGF. All of these factors a key messenger in neuron-microglia inter- might be potentially trophic for neurons and actions. might constitute a bridge between thyroid hormone and neurogenesis (for a review, see Neuron-astrocyte interactions 36). During CNS development, neurons must Role of astrocytes in neuronal development extend projections in order to establish their connections. Growing axons navigate toward The normal development of the verte- their targets in response to a variety of guid- brate nervous system entails the death of a ance signals in their surrounding environ- great quantity of the neurons originally gen- ment. These cues include diffusible attrac- erated. This naturally occurring cell death is tive or repellent molecules secreted by the regulated by the availability of specific neu- intermediate or final cellular targets of the rotrophic factors that promote neuronal sur- axons. Glial cells have been exhaustively

Braz J Med Biol Res 34(5) 2001 Neuron-glia interactions during nervous system development 615 reported as a source of asymmetric cues differences observed in their ability to sup- during axonal navigation (37). Commissural port neurite outgrowth. and decussation formation in the nervous Taken together, the above data provide system, such as the optic chiasm and the evidence that astrocyte-soluble factors play floor plate of the nervous system, is depend- an important role in several steps of neuronal ent on the interaction of growth axons and morphogenesis from the early events of neu- resident glia of these regions. Several adhe- ronal precursor proliferation until later peri- sion and soluble molecules involved in such ods of neuronal differentiation and estab- interactions have already been reported. lishment of neural circuits. Netrin-1, a -related molecule con- taining three EGF repeat motifs, is one of the Role of neuronal factors in astrocyte better known soluble signals. Netrin-1 is morphogenesis important for to the midline of the brain. Netrin-deficient mice show ad- While there is compelling evidence of ditional defects in the corpus callosum as the effects of astrocyte factors on neurons, well as hippocampal and anterior commis- their effects on astrocytes have not been sures, and have been shown to attract ven- determined. Some of our knowledge about trally decussating axons in the developing astrocyte biology came from studies of the brainstem (38). visual system. The eye provides In agreement with in vivo studies, several an interesting system to study cell-cell com- in vitro lines of evidence have implicated munication. During development, cells from astrocyte-soluble factors in neuronal mor- several different sources come together in a phogenesis. Neuronal polarity, which is cru- coordinated fashion to form the final struc- cial for neural circuits, is highly modulated ture (41). The retina itself is composed of by glial cells. Sympathetic neurons main- cells of different developmental origins, tained in vitro in the presence of astrocytes whose numbers must presumably be matched extend axons and , while in the to one another by cell-cell interactions. Most absence of astrocytes they extend solely of the cells of the neural retina are generated axons. Such dendritic neuritogenesis is in- by multipotential neuroepithelial precursors duced by bone morphogenetic proteins, a that reside near the outer surface of the retina. subclass of the TGF-ß superfamily involved In contrast, retinal astrocytes originate from in many aspects of neuronal maturation (39). the optic stalk and migrate across the inner Additional evidence for the influence of surface of the retina. The migrating astro- astrocyte-soluble factors on neuronal mor- cytes form a glial network that spreads radi- phogenesis has been provided by studies of ally in close association with the RGC axons. Garcia-Abreu et al. (6,40) who demonstrated Such invasion by astrocytes has been re- that astrocytes derived from distinct regions ported to be mediated by secretion of PDGF of the midbrain can differently modulate by RGC. This factor is expressed and se- neurite extension. Astrocytes derived from creted by RGC while PDGF receptor alpha the lateral region of the mesencephalon are (PDGFRa), an isoform of the tyrosine ki- highly permissive to neurite outgrowth, nase PDGFR, is expressed in retinal astro- whereas those derived from the midline cytes. By inhibiting PDGF signaling with a proved to be restrictive to neuritogenesis (6). neutralizing anti-PDGFRa or a soluble ex- These astrocyte populations exhibited great tracellular fragment of PDGFRa, Fruttiger heterogeneity in the content of soluble pro- et al. (42) impaired astrocyte network devel- teoglycans secreted in the medium (40). opment. Apparently, PDGF mediates a short These discrepancies may account for the paracrine interaction between RGC and as-

Braz J Med Biol Res 34(5) 2001 616 F.C.A. Gomes et al.

trocytes during retina development. 1 and GLAST expression is modulated by Besides retinal astrocyte migration, their neuronal soluble factors rather than by cell morphology is also strongly influenced by contact (50,51). RGC axons. At the periphery of the cat By using transgenic mice bearing 2 kb of retina, where RGC axons are sparse, astro- the 5’ flanking region of the astrocyte matu- cytes adopt a stellate shape in contrast to the ration marker GFAP gene linked to the ß- strongly elongated form present in RGC-rich galactosidase reporter gene, we have dem- regions. Recently, Gargini et al. (43) provid- onstrated that cortical neurons can induce ed evidence that the astrocyte axon-related the GFAP gene promoter followed by trans- morphology is induced by a signal derived genic astrocyte differentiation, by secreting from spikes. Although the nature of the as- brain region-specific soluble factors (47). trocyte trophic signal has not been identi- This event was dependent on the brain re- fied, a possibility considered by the authors gional origin of the neurons since cerebral is that it might be a released polypeptide hemisphere neuronal factors were unable to acting through astrocyte receptors. induce the GFAP gene promoter of midbrain Although neuronal effect mechanisms on and cerebellar astrocytes. Several growth astrocytes are still far from being well under- factors are putative candidates in mediating stood, increasing evidence has been accu- such effect (46). Further analysis of the GFAP mulated pointing at neurons as modulators gene promoter would contribute to the iden- of astrocyte gene expression and differentia- tification of the neuronal-derived astrocyte tion (44-47). A way to study astrocyte differ- differentiation factor. entiation is by evaluating levels of proteins whose expression patterns vary during astro- Neuron-other glial cell interactions cyte development such as the intermediate filament glial fibrillary acidic protein (GFAP) Neuron-radial glia interactions (46,47), the enzyme glutamine synthetase (48) and glutamate transporters (49), among During development of the CNS, neu- others. Two main subtypes of glutamate trans- rons are born on the ventricular surface of porters have been described in glia, i.e., the neural tube and appear to migrate to their GLAST, with expression predominating at final destination. The success of such event early stages, and GLT-1 whose expression is partially dependent on the interaction of progressively increases with maturity. postmitotic neurons and the system of radial Swanson et al. (44) have reported that neu- glial fibers, precursors of CNS astrocytes rons can modulate astrocyte glutamate trans- (52). Although this interaction is mainly porter expression in vitro. In the absence of mediated by contact and several proteins neurons, cortical astrocytes maintain polygo- involved in this process have already been nal shapes and express only the GLAST identified (4,53), there are few examples of transporter. When co-cultured with a neu- soluble factors as mediators. Hunter and ronal layer, many of the astrocytes assume a Hatten (54) have shown that the expression stellate shape and express GLT-1. These of identity in mammalian findings support the general principle that forebrain is determined by the availability of normal expression of GLT-1 protein by as- diffusible inducing signals. Although the fac- trocytes requires a neuronal signal, suggest- tor has not been completely characterized, ing that neurons can modulate astrocyte dif- biochemical studies have indicated that it is ferentiation. Although the nature of this neu- different from the neural growth regulators ronal signal remains to be identified, recent already known. Those data provide support reports have clearly demonstrated that GLT- for the role of neuronal extrinsic signals in

Braz J Med Biol Res 34(5) 2001 Neuron-glia interactions during nervous system development 617 determining and maintaining a radial glial rived neurotrophic factor indirectly increased identity and suggest that transformation of retinal bipolar cell survival in vitro by acting radial glia into astrocytes is regulated by the through p75NTR in Müller cells. The commu- availability of neuronal signals rather than nication between Müller cells and retinal by changes in cell potential (54). A remark- neurons indicates that these glial cells play able example is the presence of the gluta- an active role in retinal function. Recently, mate receptor GLAST in radial glia in the Harada et al. (58) have shown that Müller developing spinal cord (55). It is clear that cells can prevent photoreceptor degenera- glutamate transporters on mature astrocytes tion indirectly through bFGF production. play an essential role in the rapid removal of Retinal degeneration up-regulated both extracellular glutamate in order to keep the p75NTR receptor and TrkC in different parts level low enough to prevent neuronal excito- of Müller cells. Exogenous neurotrophin-3 toxicity. Although their role in radial glia is increased but nerve growth factor decreased not yet completely understood, it has been bFGF production in Müller cells which can suggested that migration may be modulated directly rescue photoreceptor apoptosis. Al- by glutamate levels along the route. Further- though bFGF is known to stimulate rat pho- more, it is also important to consider that toreceptor survival directly through FGF re- glutamate supplied by migrating neurons ceptors, the cited study demonstrated that might also be involved in differentiation of cell survival during retinal degeneration may the radial glia-astrocyte lineage. also be regulated in an indirect manner by GGF/neuregulin signaling has also been glial cells and suggests functional glial-neu- implicated in neuron-radial glial fiber inter- ronal cell interactions as new therapeutic actions. Rakic’s group (4) has shown that targets against neurodegeneration. GGF is expressed by migrating cortical neu- rons and promotes their migration along ra- Concluding remarks dial glial fibers. Concurrently, GGF also pro- motes the maintenance and elongation of Taken together, available literature data radial glial cells. In the absence of GGF support the concept that within the context signaling via erbB2 receptors radial glial of brain development, neuron-glia interac- development is abnormal. The ability of GGF tions are not of a single type, but rather to influence both neuronal migration and present great complexity and heterogeneity radial glial development in a mutually de- throughout the CNS. Currently, it is widely pendent manner suggests that it functions as accepted that neuron-glia interactions play a soluble mediator of migrating neurons and an important role in several steps of nervous radial glial cells in the developing cerebral system morphogenesis from the early stages cortex. of neurogenesis and gliogenesis to later stages of establishment of neural connections. A Neuron-Müller glia interactions dynamic interplay between neurons and glial cells undoubtedly helps to shape developing The concept of glial-neuronal cell inter- neural circuits by controlling the survival actions in the retina during development has and morphology of neurons, the growth of been extensively proposed. Fetal calf serum their axons, and the number and efficacy of stimulates the proliferation of Müller cells, their , as reported here based on which indirectly arrests rod differentiation data from different groups including ours. by releasing leukemia inhibitory factor (56). Although we have learned much about the In addition, Wexler et al. (57) recently pro- physiology of glial cells over the last ten posed a similar scheme in which brain-de- years, our knowledge of the function and

Braz J Med Biol Res 34(5) 2001 618 F.C.A. Gomes et al.

Within this context, it will be very useful Astrocyte Radial glia in the future to elucidate the mechanisms involved in neuron-glia interactions, since

PDGF GGF2 these are among the most relevant interac- Glutamate Glutamate tions neural cells will experience during de- ? ? velopment. Although several molecules in- Neuron volved in such interactions have already been TGF-ß1, BMPs, GDNF EGF identified (Figure 1), we are still in the dark GGF2 TNF-ß GGF2 concerning neuronal effects on glial cells a bFGF aFGF, bFGF TNF- TGF-ß2 PDGF Oligodendrocyte particularly those involved in astrocyte de- GDNF Glutamate Glutamate velopment. It would be worth to explore PAF gene expression in neural cells in order to

Schwann cell understand how neuron-glia interactions Microglia might modulate developmental genes during construction of the nervous system. Figure 1. Neuron-glia interactions mediated by soluble factors. Secretion of growth factors One of the most compelling lines of evi- by neurons and glial cells can mutually influence several steps of neurogenesis and dence for the role of neuron-glia interactions gliogenesis (for details, see text). TGF-ß1 and TGF-ß2, transforming growth factor ß1 and 2; TNF-a and TNF-ß, tumor necrosis factor alpha and beta; PAF, platelet-activating factor; EGF, in nervous system development was the iden- epidermal growth factor; PDGF, platelet-derived growth factor; bFGF and aFGF, basic and tification of the glial cell missing (gcm) gene acidic fibroblast growth factor; BMPs, bone morphogenetic protein family; GGF2, glial in Drosophila (60) which functions as a growth factor 2; GDNF, glial cell line-derived neurotrophic factor. binary switch that turns on glial fate while inhibiting default neuronal fate. Its mutation development of glia is still rudimentary. Sev- causes presumptive glial cells to differenti- eral growth factors involved in gliogenesis ate into neurons, whereas its ectopic expres- have been identified and this will certainly sion forces virtually all CNS cells to become be crucial for a better understanding of glial glial cells. Analysis of gcm mutants revealed, cell functions and interactions with neurons. in addition to a decreased number of glial The recent finding that subventricular astro- cells, a series of defects in several axonal cytes can act as neural stem cells in the adult tracts. Such defects were attributed mainly mammalian brain clearly highlights the new to the loss of glial signals important to ax- view of glial cells held by neurobiologists onal growth and neuronal proliferation and (59). Whereas glial cells have been regarded differentiation (60). so far as elements of structural and trophic Until recently there was no way to selec- support, today they might represent a key tively eliminate mammalian glial cells in element in neural cell origin and therefore in vivo in order to explore how the brain devel- brain development. ops and functions without them, as done in One key issue in developmental neurobiol- Drosophila after gcm identification. How- ogy is to understand how the brain orches- ever, we have taken a great step from the trates the differentiation of various cell types. passive glia described by Virchow nearly a A range of epigenetic signals are involved in century ago to the astrocyte stem cells of neural fate potential, lineage specification and today. The close association between neu- cellular differentiation in the CNS and periph- rons and glial cells during nervous system eral nervous system. Some of these signals are development suggests that deep inside these initiated very early in development due to the interactions might be hidden the secrete of diffusible factors and cell contact found in the the nervous system organization. developmental environment.

Braz J Med Biol Res 34(5) 2001 Neuron-glia interactions during nervous system development 619

References

1. Lim DA & Alvarez-Buylla A (1999). Interac- tem myelination in vivo. Journal of Neuro- 22. Cameron HA, Hazel TG & McKay RDG tion between astrocytes and adult sub- science Research, 26: 409-418. (1998). Regulation of neurogenesis by ventricular zone precursors stimulates 12. Asakura K, Hunter SF & Rodriguez M growth factors and neurotransmitters. neurogenesis. Proceedings of the Na- (1997). Effects of transforming growth Journal of Neurobiology, 36: 287-306. tional Academy of Sciences, USA, 96: factor-ß and platelet-derived growth fac- 23. Gallo V, Zhou JM, McBain CJ, Wright PW, 7526-7531. tor on oligodendrocyte precursors: in- Knutson PL & Armstrong RC (1996). Oli- 2. Barres BA (1997). Neuron-glial interac- sights gained from a neuronal cell line. godendrocyte progenitor cell proliferation tions. In: Cowan WM, Jessell TM & Journal of Neurochemistry, 68: 2281- and lineage progression are regulated by Zipursky SL (Editors), Molecular and Cel- 2290. glutamate receptor mediated K+ channel lular Approaches to Neural Development. 13. Wood PM & Bunge RP (1986). Evidence block. Journal of Neuroscience, 16: 2659- Oxford University Press, New York, 64- that axons are mitogenic for oligodendro- 2670. 107. cytes isolated from adult animals. Nature, 24. Yuan X, Eisen AM, McBain CJ & Gallo V 3. Pfrieger FW & Barres BA (1997). Synaptic 320: 756-758. (1998). A role for glutamate and its recep- efficacy enhanced by glial cells in vitro. 14. Noble M, Murray K, Stroobant P, Water- tors in the regulation of oligodendrocyte Science, 277: 1684-1686. field MD & Riddle P (1988). Platelet-de- development in cerebellar tissue slices. 4. Anton ES, Marchionni MA, Lee KF & Rakic rived growth factor promotes division and Development, 125: 2901-2914. P (1997). Role of GGF/neuregulin signal- motility and inhibits premature differen- 25. Ling EA & Wong WC (1993). The origin ing in interactions between migrating neu- tiation of the oligodendrocyte/type-2 as- and nature of ramified and amoeboid mi- rons and radial glia in the developing cere- trocyte progenitor cell. Nature, 333: 560- croglia: a historical review and current bral cortex. Development, 124: 3501- 562. concepts. Glia, 7: 9-18. 3510. 15. Grinspan JB, Edell E, Carpio DF, Beesley 26. Dobbertin A, Schmid P, Gelman M, Glo- 5. Gomes FCA, Maia CG, Menezes JRL & JS, Lavy L, Pleasure D & Golden JA winski J & Mallat M (1997). Neurons pro- Moura Neto V (1999). Cerebellar astro- (2000). Stage-specific effects of bone mote macrophage proliferation by produc- cytes treated by thyroid hormone induce morphogenetic proteins on the oligoden- ing transforming growth factor-ß2. Jour- neuronal proliferation. Glia, 25: 247-255. drocyte lineage. Journal of Neurobiology, nal of Neuroscience, 17: 5305-5315. 6. Garcia-Abreu J, Moura Neto V, Carvalho 43: 1-17. 27. Derynck R & Feng X-H (1997). TGF-ß re- SL & Cavalcante LA (1995). Regionally 16. Canoll PD, Musacchio JM, Hardy R, ceptor signaling. Biochimica et Biophy- specific properties of midbrain glia: I. In- Reynolds R, Marchionni MA & Salzer JL sica Acta, 1333: F105-F150. teractions with midbrain neurons. Journal (1996). GGF/neuregulin is a neuronal sig- 28. Noda M, Nakanishi H, Nabekura J & of Neuroscience Research, 40: 417-477. nal that promotes the proliferation and Akaike N (2000). AMPA-kainate subtypes 7. Fróes MM, Correia AHP, Garcia-Abreu J, survival and inhibits the differentiation of of glutamate receptor in rat cerebral mi- Spray DC, Campos de Carvalho AC & oligodendrocyte progenitors. Neuron, 17: croglia. Journal of Neuroscience, 20: 251- Moura Neto V (1999). Junctional coupling 229-243. 258. between neurons and astrocytes in pri- 17. Dong Z, Brennan A, Liu N, Yarden Y, 29. Aihara M, Ishii S, Kume K & Shimizu T mary CNS cultures. Proceedings of the Lefkowitz G, Mirsky R & Jessen KR (2000). Interaction between neurone and National Academy of Sciences, USA, 96: (1995). Neu differentiation factor is a neu- microglia mediated by platelet-activating 7541-7546. ron-glia signal and regulates survival, pro- factor. Genes to Cells, 5: 397-406. 8. Alvarez-Maubecin V, García-Hernández F, liferation, and maturation of rat Schwann 30. Connor B & Dragunow M (1998). The role Williams JT & Van Bockstaele EJ (2000). cell precursors. Neuron, 15: 585-596. of neuronal growth factors in neurode- Functional coupling between neurons and 18. Maurel P & Salzer JL (2000). Axonal regu- generative disorders of the . glia. Journal of Neuroscience, 20: 4091- lation of Schwann cell proliferation and Brain Research Reviews, 27: 1-39. 4098. survival and the initial events of myelina- 31. Banker GA (1980). Trophic interactions be- 9. Giulian D, Allen RL, Baker TJ & Tomozawa tion requires PI 3-kinase activity. Journal tween astroglial cells and hippocampal Y (1986). Brain peptides and glial growth. of Neuroscience, 20: 4635-4645. neurons in culture. Science, 209: 809-810. I. Glia-promoting factors as regulators of 19. Syroid DE, Maycox PR, Burrola PG, Liu N, 32. Kane CJM, Brown GJ & Phelan KD (1996). gliogenesis in the developing and injured Wen D, Lee KF, Limke G & Kilpatrik TJ Transforming growth factor-ß2 stimulates central nervous system. Journal of Cell (1996). Cell death in the Schwann cell and inhibits neurogenesis of rat cerebellar Biology, 102: 803-811. lineage and its regulation by neuregulin. granule cells in culture. Developmental 10. David S, Miller RH, Patel R & Raff MC Proceedings of the National Academy Sci- Brain Research, 96: 46-51. (1984). Effects of neonatal transection on ences, USA, 93: 9229-9234. 33. Kuhn HG, Winkler J, Kempermann G, Thal glial cell development in the rat optic 20. Meyer D & Birchmeier C (1995). Multiple LJ & Gage FH (1997). Epidermal growth nerve: evidence that the oligodendrocyte- essential functions of neuregulin in devel- factor and fibroblast growth factor-2 have type-2 astrocyte cell lineage depends on opment. Nature, 278: 386-390. different effects on neural progenitors in axons for its survival. Journal of Neurocy- 21. Shah NM, Marchionni MA, Issacs I, the adult rat brain. Journal of Neurosci- tology, 13: 961-974. Stoobant P & Anderson DJ (1994). Glial ence, 17: 5820-5829. 11. Kidd GJ, Hauer PE & Trapp BD (1990). growth factor restricts mammalian neural 34. Bruno V, Battaglia G, Casabona G, Copani Axons modulate myelin protein messen- crest stem cells to a glial fate. Cell, 77: A, Caciagli F & Nicoletti F (1998). Neuro- ger RNA levels during central nervous sys- 349-360. protection by glial metabotropic glutamate

Braz J Med Biol Res 34(5) 2001 620 F.C.A. Gomes et al.

receptors is mediated by transforming is mediated by action spike activity during Brunstrom JE (1998). New directions for growth factor-ß. Journal of Neuroscience, development. Developmental Brain Re- neuronal migration. Current Opinion in 18: 9594-9600. search, 110: 177-184. Neurobiology, 8: 45-54. 35. Oppenheim RW, Houenou LJ, Parsada- 44. Swanson RA, Liu J, Miller JW, Rothstein 53. Zhen L, Heintz N & Hatten ME (1996). nian AS, Prevette D, Snider WD & Shen L JD, Farrel K, Stein BA & Longuemare MC CNS gene encoding astrotactin, which (2000). Glial cell line-derived neurotrophic (1997). Neuronal regulation of glutamate supports neuronal migration along glial fi- factor and developing mammalian moto- transporter subtype expression in astro- bers. Science, 272: 417-419. neurons: regulation of programmed cell cytes. Journal of Neuroscience, 17: 932- 54. Hunter KE & Hatten ME (1995). Radial death among motoneuron subtypes. Jour- 940. glial cell transformation to astrocytes is nal of Neuroscience, 20: 5001-5011. 45. Hatten ME (1985). Neuronal regulation of bidirectional: Regulation by a diffusible 36. Gomes FCA, Lima FRS, Trentin AG, Mallat astroglia morphology and proliferation in factor in embryonic forebrain. Proceed- M & Moura Neto V (2000). Thyroid hor- vitro. Journal of , 100: 384- ings of the National Academy of Sciences, mone role on nervous system morpho- 396. USA, 92: 2061-2065. genesis. Progress in Brain Research (in 46. Gomes FCA, Paulin D & Moura Neto V 55. Shibata T, Yamada K, Watanabe M, press). (1999). GFAP: modulation by growth fac- Ikenaka K, Wada K, Tanaka K & Inoue Y 37. Stoeckli A & Landmesser LT (1998). Axon tors and its implication in astrocyte differ- (1997). Glutamate transporter GLAST is guidance at choice points. Current Opin- entiation. Brazilian Journal of Medical and expressed in the radial glia-astrocyte lin- ion in Neurobiology, 8: 73-79. Biological Research, 32: 615-631. eage of developing mouse spinal cord. 38. Serafini T, Colamarino SA, Leonardo ED, 47. Gomes FCA, Garcia-Abreu J, Galou M, Journal of Neuroscience, 17: 9212-9219. Wang H, Beddington R, Skarnes WC & Paulin D & Moura Neto V (1999). Neurons 56. Neophytou C, Vernallis AB, Smith A & Tessier-Lavigne M (1996). Netrin-1 is re- induce glial fibrillary acidic protein (GFAP) Raff MC (1997). Müller-cell-derived leu- quired for commissural axon-guidance in gene promoter of astrocytes derived from kaemia inhibitory factor arrests rod photo- the developing vertebrate nervous sys- transgenic mice. Glia, 26: 97-108. receptor differentiation at postmitotic pre- tem. Cell, 87: 1001-1014. 48. Kvamme E, Svenneby G, Hertz L & rod stage of development. Development, 39. Prochiantz A (1995). Neuronal polarity: giv- Schousboe A (1982). Properties of phos- 124: 2345-2354. ing neurons heads and tails. Neuron, 15: phate activated glutaminase in astrocytes 57. Wexler EM, Berkovich O & Nawy S 743-746. cultured from mouse brain. Neurochemi- (1998). Role of low-affinity NGF receptor 40. Garcia-Abreu J, Mendes FA, Onofre GR, cal Research, 7: 761-770. (p75) in survival of retinal bipolar cells. Freitas MS, Silva LCF, Moura Neto V & 49. Würdig S & Kugler P (1990). Histochemis- Visual Neuroscience, 15: 211-218. Cavalcante L (2000). Contribution of hep- try of glutamate metabolising enzymes in 58. Harada T, Harada C, Nakayama N, Oku- aran sulfate to the non-permissive role of the rat cerebellar cortex. Neuroscience yama S, Yoshida K, Kohsaka S, Matsuda H the midline glia to the growth of midbrain Letters, 130: 165-168. & Wada K (2000). Modification of glial- neurites. Glia, 29: 260-272. 50. Gegelashvili G, Dehnes Y, Danbolt NC & neuronal cell interactions prevents photo- 41. Karshing A, Wassle H & Schnitzer J Schousboe A (2000). The high-affinity glu- receptor apoptosis during light-induced (1986). Shape and distribution of astro- tamate transporters GLT1, GLAST, and retinal degeneration. Neuron, 26: 533- cytes in the cat retina. Investigative Oph- EAAT4 are regulated via different signal- 541. thalmology and Visual Science, 26: 828- ing mechanisms. Neurochemistry Inter- 59. Doetsch F, Caillé I, Lim DA, García- 831. national, 37: 163-170. Verdugo JM & Alvarez-Buylla A (1999). 42. Fruttiger M, Calver AR, Krüger WH, 51. Perego C, Vanoni C, Bossi M, Massari S, Subventricular zone astrocytes are neural Mudhar HS, Michalovich D, Takakura N, Basudev H, Longhi R & Pietrini G (2000). stem cells in the adult mammalian brain. Nishikawa SI & Richardson WD (1996). The GLT-1 and GLAST glutamate trans- Cell, 97: 703-716. PDGF mediates a neuron-astrocyte inter- porters are expressed on morphologically 60. Jones BW, Fetter RD, Tear G & Goodman action in the developing retina. Neuron, distinct astrocytes and regulated by neu- CS (1995). Glial cells missing: a genetic 17: 1117-1131. ronal activity in primary hippocampal co- switch that controls glial versus neuronal 43. Gargini C, Deplano S, Bisti S & Stone J cultures. Journal of Neurochemistry, 75: fate. Cell, 82: 1013-1023. (1998). Evidence that the influence of gan- 1076-1084. glion cell axons on astrocyte morphology 52. Pearlman AL, Faust PL, Hatten ME &

Braz J Med Biol Res 34(5) 2001