Neurotrophic factors in the primary olfactory pathway
Introduction
The olfactory system provides a rich model in which to investigate signalling molecules in neurogenesis, neuronal differentiation and migration, and neuronal cell death, processes involving interplay between genetic and epigenetic influences. Neurones in the olfactory system are produced in the two major sites of neurogenesis still present in the adult nervous system — the olfactory epithelium and the subventricular zone of the forebrain. Neurogenesis and replacement of the sensory neurones in the adult olfactory epithelium is well documented and continues throughout adult life in all vertebrates, including humans (Breipohl et al., 1986, Graziadei and Monti Graziadei, 1978, Murrell et al., 1996). Neurogenesis also continues in the subventricular zone of the forebrain producing new cells which migrate forward and differentiate into the various cell types of the olfactory bulb (Altman, 1969, Kishi, 1987, Lois and Alvarez-Buylla, 1994). Subventricular neurogenesis continues in adulthood and has been identified in rodent, primate and human (Corotto et al., 1993, Lois and Alvarez-Buylla, 1994). Neurogenesis in the adult nervous system is no doubt a highly regulated process controlled by many autocrine and paracrine signals, such as growth factors, just as it is regulated in the embryo. There must be controls on precursor proliferation and differentiation and on the survival of the progeny and there will be molecular signals regulating cellular migration and outgrowth of axons and dendrites. The primary olfactory pathway is a most suitable model to study these cellular processes because the tissue is easily accessible and can be manipulated in vivo and in vitro.
In this review, we present what is known about the distribution of growth factors and their receptors in the olfactory system, as well as the limited functional studies available. The information reviewed here has been gleaned from multiple sources. For all growth factors this data is patchy and incomplete and none of the growth factors has been studied systematically in all aspects with most information arising from single studies. Sometimes the cellular distribution of a growth factor protein may be known but more often only the tissue distribution of mRNA is reported without cellular detail. Similarly, as with much growth factor research, close analysis of the functional studies suggests that many experiments fail to distinguish between proliferation, differentiation and death of the cell types under investigation. As a result it should be realised that many conclusions about growth factor functions must remain under speculation. Despite these limitations, this review presents a picture of the olfactory system richly in the control of a variety of growth factors and provides many avenues for further exploration. An understanding of the role of growth factors will provide an insight into the plasticity of re-growth and repair that are preserved in the olfactory system. This knowledge has become very significant in view of recent developments in which olfactory ensheathing cells have been used for repair of the spinal cord (Imaizumi et al., 1998, Li et al., 1998) and in which stem cells from the subventricular zone have been applied as a source of haematopoietic stem cells (Bjornson et al., 1999).
The olfactory epithelium is a pseudo-stratified, columnar epithelium containing several cell types: sensory neurones at different stages of differentiation, the supporting cell, the globose basal cell, and the horizontal basal cell. Cells within the olfactory epithelium can be identified by a variety of immunological markers, for example, a defining marker for the supporting cell, a glial-like cell, is SUS1 (Hempstead and Morgan, 1983). Among the neural elements of the epithelium, the most easily defined is the olfactory sensory neurone which expresses olfactory marker protein (Margolis, 1985). Immature and mature neurones express neurone-specific β-tubulin and neural cell adhesion molecule (NCAM) (Calof and Chikaraishi, 1989, Key and Akeson, 1990, Lee and Pixley, 1994). All globose basal cells are identified with the antibodies GBC1-3 (Goldstein and Schwob, 1996). Globose basal cells early in the lineage express mMsi (Sakakibara et al., 1996) and later, MASH1 (Cau et al., 1997, Gordon et al., 1995, Guillemot and Joyner, 1993). Deepest in the epithelium, lining the basement membrane, is the horizontal basal cell which expresses keratin and a surface glycoprotein which binds to the lectin BS-I (Holbrook et al., 1995). This cell is thought by some to be the stem cell for olfactory neurogenesis (Calof and Chikaraishi, 1989, Satoh and Takeuchi, 1995). As cells pass through the lineage from stem cell to mature sensory neurone they pass through the stages identified by these immunological markers, although the precise relations between lineage and specific markers is disputed (e.g. Goldstein and Schwob, 1996) (Fig. 1).
It is generally accepted that new neurones arise from proliferation and differentiation of basal cells (Graziadei and Dehan, 1973, Moulton et al., 1970). Basal cell mitosis occurs in two phases, slow and rapid, analogous to the synthetic and growth phases of the developing nervous system (Mackay-Sim and Kittel, 1991a). It is suggested that a presumptive stem cell divides asymmetrically every 50 days producing another stem cell, which stays close to the basement membrane, and a neuronal precursor which divides rapidly several times producing many immature neurones which migrate away from the basement membrane as they differentiate (Mackay-Sim and Kittel, 1991a). The identity of the putative stem cell and its lineage among the globose and horizontal basal cells is in dispute. In vivo quantitative analysis suggested that a stem cell resides on the basement membrane, in the location of the horizontal basal cell (Mackay-Sim and Kittel, 1991a) and in vitro experiments suggested that neurones can arise from the horizontal basal cell (Mahanthappa and Schwarting, 1993, Satoh and Takeuchi, 1995). In contrast, in vivo retro-viral labelling of proliferating cells suggested that neurones arise only from the globose basal cells (Caggiano et al., 1994, Schwob et al., 1994). This issue is yet to be resolved satisfactorily as there is no direct evidence linking immunological phenotype with a role as stem cell.
Neurogenesis can be stimulated in the olfactory epithelium by causing the death of the sensory neurones. This is commonly done experimentally by cutting the olfactory nerves or removing the olfactory bulb, a procedure known as ‘bulbectomy’. When the olfactory nerves are damaged in this way there is a massive wave of neuronal apoptosis in the olfactory epithelium (Holcomb et al., 1995, Michel et al., 1994), an exponential increase in basal cell mitosis (Camara and Harding, 1984) followed by restitution of the sensory neurones (Graziadei and Monti Graziadei, 1979). Chemical destruction of the sensory neurones also leads to their loss and replacement (Harding et al., 1978, Hurtt et al., 1988, Rehn et al., 1981).
The olfactory epithelium appears to be in a dynamic equilibrium between basal cell birth, neuronal differentiation and apoptosis. This equilibrium is presumably regulated by autocrine and paracrine signals which stimulate or inhibit proliferation, differentiation and cell survival. Some of these signals are, no doubt, peptide growth factors. Although some cells die as soon as 24 h after division (Carr and Farbman, 1992, Holcomb et al., 1995), the majority of developing neurones die about 2 weeks later (Breipohl et al., 1986, Hinds et al., 1984, Mackay-Sim and Kittel, 1991a, Moulton et al., 1970). Those that survive this period can survive for many months (Breipohl et al., 1986, Hinds et al., 1984, Mackay-Sim and Kittel, 1991a, Moulton et al., 1970). In vivo the rate of neurogenesis varies with local epithelial thickness (Mackay-Sim et al., 1988, Mackay-Sim and Patel, 1984), age (Weiler and Farbman, 1997), and patency of the external nares (Farbman et al., 1988, Maruniak et al., 1989).
Olfactory neurogenesis continues in the adult human olfactory epithelium into old age (Féron et al., 1998, Murrell et al., 1996) and continuous cell lines have been isolated from the human olfactory epithelium (Ensoli et al., 1998, Wolozin et al., 1992).
The olfactory bulb is a ovoid-shaped, layered structure forming the most rostral end of the forebrain. The outer layer is formed by the axons of the olfactory sensory neurones which enter the central nervous system accompanied by their characteristic glia, the olfactory nerve ensheathing cells. Sensory axons terminate in specialised structures called glomeruli within which they synapse with the output neurones of the olfactory bulb, the mitral and tufted cells. Also contributing to the neuropil of the glomeruli are the processes of the periglomerular neurones whose cells bodies make up the bulk of the glomerular layer. Beneath the glomeruli is the external plexiform layer comprised of cell bodies of some interneurones and tufted cells, but mainly composed of processes of mitral cells and granule cells. The layer of mitral cell bodies is interleaved between the external and internal plexiform layers which encloses the granule cells, the most populous cells of the olfactory bulb. Axons of the mitral and tufted cells run to the ‘core’ of this structure before proceeding caudally and moving ventrolaterally to form the lateral olfactory tract. Within this tract are axons from other regions of the brain which project into the olfactory bulb. For an extensive review of the structure and function of the olfactory bulb, see Halasz (1990) (Fig. 2).
The olfactory bulb develops as an evagination of the rostral end of the telencephalon soon after the first olfactory axons have grown into this region. Compared to many other species, the process of neurogenesis in the mouse olfactory system is perhaps the best documented (Hinds, 1968b). As in other mammalian embryos, neurogenesis consists of a sequence of events in which the largest neurones are generated first followed by the intermediate-sized, and then the smallest ones. At E12 neurogenesis of the largest neurones, the mitral cells, occurs prior to the appearance of an obvious outgrowth from the forebrain. Mitotic figures are observed in the ventricular layer and newly formed mitral cells subsequently migrate out radially to their definitive positions over a period of 3 days. During this time, tufted cells undergo their final cell division and they soon migrate past the mitral cells to take up residence in the external plexiform layer. Among the tufted cells, the smallest ones are produced last and they eventually take up a more superficial location. The last neurones to appear are the small periglomerular and granule cells most of which are generated in the subependymal layer postnatally, reaching a peak during the second week and extending as late as the end of the third week (Bayer, 1983, Hinds, 1968b, Rosselli-Austin and Yanai, 1989).
As the olfactory bulb develops, the relative position of the ventricle recedes and becomes more caudal. Consequently, the wave of newly generated granule cells has to migrate rostrally from the subventricular zone into the bulb, forming the ‘rostral migratory stream’ (Kishi, 1987, Luskin, 1993). It has been noted that a caudorostral gradient of proliferation was present within this migratory stream (Frazier-Cierpial and Brunjes, 1989). In the rat during the first 10 postnatal days the stream enters the bulb as a massive column of cells, but thereafter it decreases progressively (Frazier-Cierpial and Brunjes, 1989). During adult life populations of interneurones continue to be generated from the subventricular zone, maintaining the migratory stream during adult life giving rise to the major types of interneurones, the granule cells and periglomerular cells (Altman, 1969, Altman and Das, 1966, Corotto et al., 1993, Gritti et al., 1999, Gritti et al., 1996, Hinds, 1968a, Kaplan et al., 1985, Lois and Alvarez-Buylla, 1994, Luskin, 1993, Weiss et al., 1996b).
Neuroglia arise from scattered proliferating glioblasts originally derived from the periventricular germinal layer. In mouse the wave of proliferation signifying the genesis of glia cells takes place late during gestation (E17) and extends up to 10 days postnatally (Hinds, 1968b). Using -thymidine labelling it was demonstrated that a high proliferation rate was first observed soon after birth in the granule cell layer followed by another wave of division in the glomerular and olfactory nerve layer a few days later (Frazier-Cierpial and Brunjes, 1989).
There has been increasing interest in recent years in olfactory ensheathing cells with properties thought to be unique among the glia. Olfactory ensheathing cells originate from the olfactory placode (Chuah and Au, 1991, Norgren et al., 1992) and are found in association with olfactory nerves in the periphery as well as in the outermost layer of the olfactory bulb (Doucette, 1991, Doucette, 1993). Studies have shown that olfactory ensheathing cells share some common features with astrocytes and peripheral Schwann cells. Like astrocytes they express glial fibrillary acidic protein (GFAP) (Barber and Lindsay, 1982), while at the same time they resemble Schwann cells morphologically and demonstrate the presence of the Schwann cell-specific protein Po (Norgren et al., 1992). Cytoplasmic processes of ensheathing cells envelope bundles of olfactory axons as they grow towards the olfactory bulb and once there they contribute to the glia limitans (Doucette, 1991). The existence of olfactory ensheathing cells in both the central and the peripheral nervous system is particularly remarkable given the commonly accepted dogma that peripheral and central glia normally do not co-exist in the same environment.
Olfactory ensheathing cells of neonatal and adult rodents have been characterised in tissue culture (Chuah and Au, 1993, Pixley, 1992, Ramon-Cueto and Nieto-Sampedro, 1992, Sonigra et al., 1999). Cells of different structural features and antigenic properties have been reported. In tissue culture, populations of ensheathing cells are known to express GFAP (Ramon-Cueto and Nieto-Sampedro, 1992; Doucette and Devon, 1995), S-100 (Chuah and Au, 1993, Pixley, 1992), p75 neurotrophin receptor (p75NTR) (Gong et al., 1994, Pixley, 1992)], NCAM (Chuah and Au, 1993) and N-cadherin (Chuah and Au, 1994). The existing data indicate that olfactory ensheathing cells possess a heterogeneous antigenic profile both in vivo and in vitro and some markers may predominate or disappear depending upon the physiological state (Doucette and Devon, 1995, Franceschini and Barnett, 1996, Li et al., 1998, Sonigra et al., 1999).
The putative importance of ensheathing cells in modulating axon growth has been attributed to their expression of several growth promoting molecules e.g. NCAM, L1, laminin and fibronectin (Gong and Shipley, 1996, Liesi, 1985, Miragall et al., 1989), which are also known to mediate fasciculation and neurone–glia interaction (Lemmon et al., 1989). There is evidence that ensheathing cells produce soluble growth factors which exert both an autocrine and paracrine effects (Woodhall et al., 1999).
Growth factors and cytokines originally refer to proteins or peptides normally found in the serum component of blood and which exert highly specific effects in very low concentrations. For each type of growth factor, there is a specific receptor or set of receptors which may be present on membranes of target cells and these convey signals via tyrosine kinases and other second messenger systems. Other types of molecules, for example, steroid hormones can also function as growth factors, acting on intracellular receptors. The definition of what constitutes a growth factor has widened considerably with the discovery of increasing types of molecules capable of regulating proliferation, differentiation and cell death. The range of responding cells varies with each growth factor, for example PDGF can act on fibroblasts, smooth muscle and neuroglia. Many growth factors were originally identified by their ability to promote the survival of developing cells. However, recent studies have indicated that they also play a role in influencing division and differentiation of progenitor cells and possibly their phenotypic traits throughout life. The overall picture of the functions of growth factors is increasingly complex: neurones can require different growth factors at specific stages of development and can require several growth factors simultaneously.
In general, activated Trk receptors are involved in initiating a cascade of intracellular cytoplasmic signals that eventually influence nuclear activity of the cell. The first step in activation following neurotrophin binding is the formation of dimers and activation of their tyrosine kinase activity. The resulting phosphotyrosine residues in turn catalyse the formation of large signalling complexes, one of which is the MAPK pathway (Heumann, 1994). In this pathway, the adapter protein Shc acts as an intermediate linking Trk phosphotyrosine residue with p21ras. Once ras is activated, it in turn activates raf the initial member of the MAPK cascade. This sets up a series of downstream activation involving sequentially MEK, MAP kinases and the protein kinase p90rsk. The activated latter two kinases are translocated to the nucleus where they phosphorylate a number of transcription factors causing rapid and long-lasting changes in specific gene expression (Segal and Greenberg, 1996).
The receptor serine–threonine kinases are a group of signalling molecules involved in development, tissue re-growth and repair. As their name suggests they have, as their distinguishing characteristic, highly conserved serine–threonine residues in their intracellular domains (Hogan, 1996, Kingsley, 1994, Massague, 1996, Ten Dijke et al., 1998). All receptor serine–threonine kinases are considered members of the TGFβ superfamily of receptors (Massague, 1996, Ten Dijke et al., 1998). This receptor family is composed of two parts, type I and type II receptors and each member of the TGFβ superfamily binds to a specific combination of type I and II receptors, both of which are required for activation (Heldin et al., 1997). Phosphorylation and subsequent activation of cytoplasmic mediators known as pathway-restricted SMADs take place following the formation of the receptor complex (Kretzschmar et al., 1997). The activated SMADs interact with Smad4 and translocate to the nucleus where they alter transcription in the target cell.
Although the pathways through which neurotrophins and cytokines act have been described separately in this section, recent studies have indicated that there may be cross-talk between these different pathways. For example, activation of MAPK was recently shown to result in phosphorylation of one of the SMAD proteins (Kretszschmar et al., 1997).
The effects of cytokines are first mediated by binding with the α component of the GP130 receptor, triggering its association with two transmembrane β components (Stahl et al., 1990). The formation of this tripartite receptor complex following ligand binding, leads to the phosphorylation and activation of the cytoplasmic protein tyrosine kinases belonging to the Janus kinase family (JAK). As a result of their phosphorylation, a family of transcription factors known as signal transducers and activators of transcription (STAT) is able to recognise the receptor complex. The STATs are in turn phosphorylated, dimerised and translocated to the nucleus where they bind to specific DNA sites to regulate gene expression (Darnell et al., 1994, Symes et al., 1994).
Section snippets
Hepatocyte growth factor
Hepatocyte growth factor (HGF), also known as scatter factor (SF), is normally released into the interstitium as an inactive single chain precursor, pro-HGF/SF which subsequently undergoes proteolytic conversion into the biologically active form of HGF/SF (Naka et al., 1992). This process of activation may be mediated by the urokinase-type plasminogen activator, tissue-type plasminogen activator (tPA) or a type of protease related to blood coagulation factor XII (Mars et al., 1995). Following
Conclusions
This review has demonstrated the very large number of growth factors which could potentially play roles in the dynamic regulation of neurogenesis, differentiation and survival occurring in the primary olfactory pathway. Despite the large amount of evidence reviewed here, there are few systematic studies which reveal the autocrine or paracrine signalling pathways involved. For most growth factors there are many pieces of evidence still necessary to establish their functions in the olfactory
Acknowledgements
Alan Mackay-Sim is supported by a Senior Biomedical Fellowship from the Garnett Passe and Rodney Williams Memorial Foundation.
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3.28 - Regeneration of the Olfactory Epithelium
2020, The Senses: A Comprehensive Reference: Volume 1-7, Second Edition