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Postnatal histogenesis in the peripheral nervous system
Int. J. Devl Neuroscience 20 (2002) 475–479
Review
Postnatal histogenesis in the peripheral nervous system Stefano Geuna a,∗ , Paolo Borrione a , Guido Filogamo b a
Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Ospedale San Luigi, Regione Gonzole 10, 10043 Orbassano, TO, Italy b Dipartimento di Anatomia, Farmacologia e Medicina Legale, Università di Torino, Torino, Italy Received 12 June 2002; accepted 12 June 2002
Abstract The issue of postnatal neurogenesis has gained great importance over the last few years and the recent amazing scientific advancements, changing our viewpoint on the long-lasting “no new neurons” dogma, have opened promising new perspectives on the treatment of the damaged nervous system. While most of the researchers have focused on the central nervous system, the peripheral nervous system has received little attention so far with respect to postnatal histogenesis. To attract scientific attention on this issue, the present article was written with the aim of reviewing the body of literature on postnatal histogenesis in the various districts of the peripheral nervous system, from the historical roots to the most recent reports. © 2002 ISDN. Published by Elsevier Science Ltd. All rights reserved. Keywords: Postnatal neurogenesis; Adult stem cells; Peripheral nervous system; Myenteric neurons; Spinal ganglia
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Postnatal histogenesis in the peripheral sensory systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Postnatal histogenesis in the autonomic nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Discussion and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction The issue of the postnatal histogenesis in the nervous system has been a subject of great interest among neuroscientists for over 100 years. Some of the fathers of modern neurobiology, such as Giuseppe Levi and Santiago Ramon y Cajal, have provided a personal contribution to this issue. Levi, at the end of the 19th century (Levi, 1896, 1898), described mitotic nerve cells in the adult rat cortex after brain damage thus suggesting the possibility that neurogenesis can occur also in adult life. On the other hand Santiago Ramon y Cajal adopted the view that “nerve paths are fixed, final and immutable” and nothing may be regenerated in the postnatal nervous system (Cajal, 1928). In his view, the reserve of cells capable of dividing and differentiating is soon exhausted in ∗ Corresponding author. Tel.: +39-11-67-08-135; fax: +39-11-90-38-639. E-mail address: [email protected] (S. Geuna).
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the nervous system and postnatal neurons only maintain the faculty of increasing their size and making new functional circuits. The debate on adult neurogenesis finds its origin at the end of the 19th century when Giulio Bizzozero, in his address delivered before the General Meeting of the XIth International Medical Congress held in Rome in 1894, coined a classification of tissues based on the growth, renewal and regeneration potential of cells (Bizzozero, 1894) that has represented a very popular framework for scientists all along the 20th century (Majno and Joris, 1996). Bizzozero divided tissues into three categories: (1) tissues with transient elements (elementi labili), that are made up by cells which continue to multiply throughout the life of the individual (e.g. the epithelial coverings); (2) tissues with stable elements (elementi stabili) that are made up by cells which although have in their normal adult state the character of stability, they have not lost the faculty of multiplying themselves when the necessity for doing so arises (e.g. the parenchyma of liver); (3) tissues with perennial elements (elementi perenni)
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that are made up by cells that, in adult life, have definitively lost the faculty of multiplying themselves. Neurons were ascribed to the latter category and, as a consequence, for many years adult neurogenesis was denied by the neuroscience community. The recent scientific advancements have undermined the “no new neurons” dogma based on Bizzozero’s classification and Cajal’s writings leading to our present view on this issue (Brazelton et al., 2000; Mezey and Chandross, 2000; Mezey et al., 2000; Sanchez-Ramos et al., 2000; Woodbury et al., 2000; Geuna et al., 2001; Gökhan and Mehler, 2001). However, most of the scientific attention have been paid to neurogenesis in the central nervous system (CNS) because of the prospects for the translation of scientific advancements to treatment of many severe brain diseases such as Parkinson and Alzheimer, whilst few researchers have addressed the issue of postnatal histogenesis in the peripheral nervous system (PNS). This review article was thus written with the aim of overviewing the body of literature on this issue starting from the pioneering papers, that in the first part of the 20th century already reported postnatal neuron addition in some PNS districts, and arriving to the most recently published reports.
on using both traditional model-based and new design-based counting methods. Other interesting studies have been published on this issue over the last few years. Bergman and Ulfhake (1998) reported a decrease in the number of DRG neurons in the very old rat (30 months) whilst Mohammed and Santer (2001) revealed that rat DRG cell number do not change during adult life and stated that the existence of neurogenesis of DRG cells in adult rats cannot be supported. On the other hand, Namaka et al. (2001) showed that early postnatal DRGs contain neural precursors that appear to proliferate in vitro in response to various factors and can then be induced to differentiate into neurons. It seems therefore that the last word on neurogenesis in adult DRGs cannot be said yet and more research is definitely needed on this issue (Geuna et al., 2000). A special mention deserves the olfactory neuroepithelium where high postnatal proliferation activity persists all along adult life. In fact, the basal cells of the olfactory neuroepithelium have been identified as a long-term stem cell compartment. These precursor elements can differentiate into mature olfactory receptor neurons which undergo a continuous renewal process, during all the animal life, with a period cycle of about 3 weeks (Moulton et al., 1970; Graziadei and Monti-Graziadei, 1978, 1979; Samanen and Forbes, 1984).
2. Postnatal histogenesis in the peripheral sensory systems The issue of neurogenesis in adult dorsal root ganglia (DRG) has been addressed by a number of studies all over the 20th century and the debate on its existence has been recently raised again on the basis of several reports in support or against it. Hatai, in 1902, was the first who reported a study that investigated age-related changes in the number of sensory neurons in mammals (rat). Though this author concluded that the total number of DRG neurons remains approximately constant with age, data reported in his paper (that were obtained from four animals only) showed a clear increase in cell counts from 1- to 5-month-old rats. From then on, other authors have addressed this issue providing data for and against the existence of an age-related increase in the number of DRG neurons in mammals. In particular, an age-related increase in DRG neurons was shown in the rabbit (Sosa and de Zorrilla, 1966), in the cat (Tessler et al., 1985) and in the rat (Cavanaugh, 1951; Devor and Govrin-Lippmann, 1985; Devor et al., 1991). In contrast with these results, Coggeshall and co-workers, using a modern design-based counting method (the disector), provided data in favour of the absence of neurogenesis in adult rat DRGs (La Forte et al., 1991; Pover et al., 1994). In these authors’ view, the previous results that supported the existence of this phenomenon were based on the employment of biased counting methods. However, evidence supporting the existence of an age-related increase in DRG neurons in the rat has been provided again more recently by Cecchini et al. (1995), Ciaroni et al. (2000), and Popken and Farel (1997). The latter study was carried
3. Postnatal histogenesis in the autonomic nervous system The Auerbach’s myenteric plexus is the autonomic nervous system site that attracted more interest from the neuroscientists all along the 20th century. The first evidence of postnatal histogenesis of myenteric neurons was provided in 1913 by Miura in the rat small intestine under pathological conditions. About 30 years later, Bennighoff (1951) studied the behavior of myenteric ganglia in the intestinal loops upstream from a sub-total stenosis induced by ligation of the rat gut and demonstrated that, together with smooth muscle hypetrophy, an increase in the size and number of ganglionic cell bodies of the Auerbach’s and Meissner’s plexuses was also evident. Few years later Filogamo and Vigliani (1953, 1954) repeated the Benninghoff experiment in dogs carrying on extensive statistical assessment of the correlation between the size of the innervation territory and the number of myenteric neurons. These in depth studies demonstrated that neuron hypertrophy is not the only feature of the adaptive process that occurs in the intestinal loops upstream from the partial obstruction. In fact, a significant increase of nerve cell number was also detected. Since there was no evidence of mitotic nerve cells, the observed increase in the number of neurons has been attributed to the persistence in the adult Auerbach’s plexus of poorly differentiated or undifferentiated cells capable of turning into neurons under the influence of exceptional stimuli. This process of cell recruitment leads to a four–five-fold increase in the number of differentiated neurons in the myenteric ganglia. Some of the newborn
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neurons also give rise to new small ganglia as demonstrated by a significant increase in the number of ganglia. The experimental induction of hypotrophy in the intestinal loops upstream from the stenosis by means of the Thiry–Vella method (i.e. the surgical exclusion of an intestinal tract from the transit connecting it to the abdominal wall) showed that a dramatic reduction of the functional stimulation to meynteric neurons, that have been previous hyperstimulated, leads to a relevant decrease in the cell body size but not in the number of neurons (Filogamo and Lievre, 1955). In support of the view that undifferentiated progenitor cells persist along adulthood in myneteric ganglia is the recent demonstration that nestin, an intermediate filament protein that is considered a specific marker of neural progenitor cell, is expressed in the postnatal myenteric plexus (Silva et al., 2000). In contrast to the above mentioned reports, it should be noted that the occurrence of adult neurogenesis in the autonomic nervous system has been denied by Gabella (1984) who failed to detect it even under conditions of enhanced functional stimulation. Finally, a more recent series of papers on the same experimental model have shown that unscheduled DNA synthesis (i.e. not followed by cell division) occurs in some myenteric neurons from the hypertrophic loops. In fact, while autoradiography after 3 H-thymidine administration and PCNA immuno-staining showed the presence DNA neosynthesis in myenteric neurons (Giacobini-Robecchi et al., 1985, 1988; Poncino et al., 1991; Corvetti et al., 2001) cytophotometry after Feulgen staining suggested that this neosynthesis not associated with cell division but with a hyperdiploid DNA content (Giacobini-Robecchi et al., 1988; Poncino et al., 1991). In addition, electrophoretic analysis of the total genomic DNA extracted from myenteric ganglia isolated from hypertrophic loops have shown the presence of extra-bands migrating below the high molecular weight DNA, suggesting that DNA amplification can be the mechanism of the observed unscheduled DNA synthesis (Giacobini-Robecchi et al., 1995). Another demonstration of the possibility that neuron addition takes place in the postnatal autonomic nervous system has been provided using an experimental model represented by the denervation of the gut by means of the benzalkonium chloride (BAC) (Sato et al., 1978; Sakata et al., 1979). Local application of BAC to an intestinal tract induces the selective destruction of about 90% of the neurons of the Auerbach’s plexus. After few weeks, a significant increase (two–five-fold) in the mean neuronal density in the small ganglia located along the mesenteric nerves can be detected (Cracco and Filogamo, 1993). It should be noted that the location of mesenteric nerves represents the migration pathway of the neural crest cells that colonize the gut during development. Similarly to what detected in the loops upstream from a partial obstruction, mitoses were not observed thus suggesting that neuronal addition along mesenteric nerves of BAC-treated animals is due to the late differentiation of a pool of neural-crest derived elements that persisted, as un-
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differentiated precursors, along the developmental migration pathway. Williams and Jew (1991) have proposed that the late differentiation of neural-crest-derived precursors can be triggered by diffusible factors originated from the intestinal wall treated by the BAC where profound degenerative and regenerative processes take place. The same can be true also in the case of neuronal addition occurring in the myenteric plexus of the loops upstream from a sub-total intestinal stenosis (Filogamo and Vigliani, 1953; Filogamo, 1987). The existence of diffusible factors that stimulate neuronal differentiation can be deduced also by the observation that the PC12 cells transplanted in the intestinal wall of BAC-treated animals rapidly give rise to long filaments and differentiate into mature neurons (Filogamo and Cracco, 1995). Further evidence on the postnatal histogenesis in enteric nervous system comes from clinical studies that have shown that intestinal inflammation induces an increase in the number of neurons in the myenteric ganglia (Storsteen et al., 1953; Davis et al., 1955). Sharkey and Parr (1996) have recently revised the literature on this issue asking a question on how there can be more enteric neurons if these cells are postmitotic? They give an answer to this question suggesting that, since cell division in adult neurons is unlikely, the possible explanation for neuron addition in adulthood is that there are precursors cells in myenteric ganglia capable of late proliferation into adult neurons (Sharkey and Parr, 1996). As regards other sites of the autonomic nervous system, experimental data are poor though, similarly to what happens to the myenteric nervous system, the presence of a compartment of reserve progenitors cells has been reported in sympathetic ganglia (Celestino da Costa, 1939; Picard and Chambost, 1953).
4. Discussion and conclusions The issue of adult neurogenesis is very much in the news (both scientific and popular) now and great hopes are arising from the public about the therapeutic potential of adult neural stem cells. Most of the interest has been directed to the CNS and only little attention has been paid to postnatal histogenesis in the PNS, an issue that, in our opinion, deserves much more research. We hope that the overview of the literature provided in this article support our viewpoint. In particular we would like to focus on a feature that is shared by both sensory and autonomic neurons and that can be important for the understanding of the basic mechanisms of adult neurogenesis in the PNS: all these neurons originate from neural crest cells that early migrated form the neural tube during development. Neural crest migratory cells also give rise to cell populations belonging to many other organs such as the heart (Farrel et al., 1999). Cardiac neural crest cells partecipate in the development of the cardiac outflow septation and pattering of the great arteries and in the formation of the cardiac conducting cells (Filogamo et al., 1990). It has been recently demonstrated by Kirby
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and co-workers that the absence of cardiac neural crest cells leads to primary myocardial disfunction (Farrel et al., 1999) and a clinical condition (DiGeorge syndrome) associated to defects in organs and tissues that depend on contributions by cell populations derived from neural crest has also been described in the human (Farrel et al., 1999). The experimental and clinical evidence briefly outlined along this article led us to tentatively advance a working hypothesis that draw together the various elements arising from more than one century of studies: we suggest that neural crest cells, besides driving the development of many different tissue and organs during development, can play a role also in the post-developmental period of animal life because some of the migratory elements persist as peripherical reserve pool of multipotent stem cells that can undergo a late differentiation into mature cells. The recruitment of this reserve pool, that probably undergo a progressive age-related exhaustion (Filogamo and Cracco, 1995), is stimulated by various physiological and pathological conditions in which new cells are needed. If this were true, it would be foreseen that the employment of neural-crest-derived cells can become a powerful therapeutic tool in the hands of the clinicians for treating various degenerative diseases affecting the peripheral nervous system.
Acknowledgements This work was supported by grants from the MURST/ MIUR.
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Review
Postnatal histogenesis in the peripheral nervous system Stefano Geuna a,∗ , Paolo Borrione a , Guido Filogamo b a
Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Ospedale San Luigi, Regione Gonzole 10, 10043 Orbassano, TO, Italy b Dipartimento di Anatomia, Farmacologia e Medicina Legale, Università di Torino, Torino, Italy Received 12 June 2002; accepted 12 June 2002
Abstract The issue of postnatal neurogenesis has gained great importance over the last few years and the recent amazing scientific advancements, changing our viewpoint on the long-lasting “no new neurons” dogma, have opened promising new perspectives on the treatment of the damaged nervous system. While most of the researchers have focused on the central nervous system, the peripheral nervous system has received little attention so far with respect to postnatal histogenesis. To attract scientific attention on this issue, the present article was written with the aim of reviewing the body of literature on postnatal histogenesis in the various districts of the peripheral nervous system, from the historical roots to the most recent reports. © 2002 ISDN. Published by Elsevier Science Ltd. All rights reserved. Keywords: Postnatal neurogenesis; Adult stem cells; Peripheral nervous system; Myenteric neurons; Spinal ganglia
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Postnatal histogenesis in the peripheral sensory systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Postnatal histogenesis in the autonomic nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Discussion and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction The issue of the postnatal histogenesis in the nervous system has been a subject of great interest among neuroscientists for over 100 years. Some of the fathers of modern neurobiology, such as Giuseppe Levi and Santiago Ramon y Cajal, have provided a personal contribution to this issue. Levi, at the end of the 19th century (Levi, 1896, 1898), described mitotic nerve cells in the adult rat cortex after brain damage thus suggesting the possibility that neurogenesis can occur also in adult life. On the other hand Santiago Ramon y Cajal adopted the view that “nerve paths are fixed, final and immutable” and nothing may be regenerated in the postnatal nervous system (Cajal, 1928). In his view, the reserve of cells capable of dividing and differentiating is soon exhausted in ∗ Corresponding author. Tel.: +39-11-67-08-135; fax: +39-11-90-38-639. E-mail address: [email protected] (S. Geuna).
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the nervous system and postnatal neurons only maintain the faculty of increasing their size and making new functional circuits. The debate on adult neurogenesis finds its origin at the end of the 19th century when Giulio Bizzozero, in his address delivered before the General Meeting of the XIth International Medical Congress held in Rome in 1894, coined a classification of tissues based on the growth, renewal and regeneration potential of cells (Bizzozero, 1894) that has represented a very popular framework for scientists all along the 20th century (Majno and Joris, 1996). Bizzozero divided tissues into three categories: (1) tissues with transient elements (elementi labili), that are made up by cells which continue to multiply throughout the life of the individual (e.g. the epithelial coverings); (2) tissues with stable elements (elementi stabili) that are made up by cells which although have in their normal adult state the character of stability, they have not lost the faculty of multiplying themselves when the necessity for doing so arises (e.g. the parenchyma of liver); (3) tissues with perennial elements (elementi perenni)
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that are made up by cells that, in adult life, have definitively lost the faculty of multiplying themselves. Neurons were ascribed to the latter category and, as a consequence, for many years adult neurogenesis was denied by the neuroscience community. The recent scientific advancements have undermined the “no new neurons” dogma based on Bizzozero’s classification and Cajal’s writings leading to our present view on this issue (Brazelton et al., 2000; Mezey and Chandross, 2000; Mezey et al., 2000; Sanchez-Ramos et al., 2000; Woodbury et al., 2000; Geuna et al., 2001; Gökhan and Mehler, 2001). However, most of the scientific attention have been paid to neurogenesis in the central nervous system (CNS) because of the prospects for the translation of scientific advancements to treatment of many severe brain diseases such as Parkinson and Alzheimer, whilst few researchers have addressed the issue of postnatal histogenesis in the peripheral nervous system (PNS). This review article was thus written with the aim of overviewing the body of literature on this issue starting from the pioneering papers, that in the first part of the 20th century already reported postnatal neuron addition in some PNS districts, and arriving to the most recently published reports.
on using both traditional model-based and new design-based counting methods. Other interesting studies have been published on this issue over the last few years. Bergman and Ulfhake (1998) reported a decrease in the number of DRG neurons in the very old rat (30 months) whilst Mohammed and Santer (2001) revealed that rat DRG cell number do not change during adult life and stated that the existence of neurogenesis of DRG cells in adult rats cannot be supported. On the other hand, Namaka et al. (2001) showed that early postnatal DRGs contain neural precursors that appear to proliferate in vitro in response to various factors and can then be induced to differentiate into neurons. It seems therefore that the last word on neurogenesis in adult DRGs cannot be said yet and more research is definitely needed on this issue (Geuna et al., 2000). A special mention deserves the olfactory neuroepithelium where high postnatal proliferation activity persists all along adult life. In fact, the basal cells of the olfactory neuroepithelium have been identified as a long-term stem cell compartment. These precursor elements can differentiate into mature olfactory receptor neurons which undergo a continuous renewal process, during all the animal life, with a period cycle of about 3 weeks (Moulton et al., 1970; Graziadei and Monti-Graziadei, 1978, 1979; Samanen and Forbes, 1984).
2. Postnatal histogenesis in the peripheral sensory systems The issue of neurogenesis in adult dorsal root ganglia (DRG) has been addressed by a number of studies all over the 20th century and the debate on its existence has been recently raised again on the basis of several reports in support or against it. Hatai, in 1902, was the first who reported a study that investigated age-related changes in the number of sensory neurons in mammals (rat). Though this author concluded that the total number of DRG neurons remains approximately constant with age, data reported in his paper (that were obtained from four animals only) showed a clear increase in cell counts from 1- to 5-month-old rats. From then on, other authors have addressed this issue providing data for and against the existence of an age-related increase in the number of DRG neurons in mammals. In particular, an age-related increase in DRG neurons was shown in the rabbit (Sosa and de Zorrilla, 1966), in the cat (Tessler et al., 1985) and in the rat (Cavanaugh, 1951; Devor and Govrin-Lippmann, 1985; Devor et al., 1991). In contrast with these results, Coggeshall and co-workers, using a modern design-based counting method (the disector), provided data in favour of the absence of neurogenesis in adult rat DRGs (La Forte et al., 1991; Pover et al., 1994). In these authors’ view, the previous results that supported the existence of this phenomenon were based on the employment of biased counting methods. However, evidence supporting the existence of an age-related increase in DRG neurons in the rat has been provided again more recently by Cecchini et al. (1995), Ciaroni et al. (2000), and Popken and Farel (1997). The latter study was carried
3. Postnatal histogenesis in the autonomic nervous system The Auerbach’s myenteric plexus is the autonomic nervous system site that attracted more interest from the neuroscientists all along the 20th century. The first evidence of postnatal histogenesis of myenteric neurons was provided in 1913 by Miura in the rat small intestine under pathological conditions. About 30 years later, Bennighoff (1951) studied the behavior of myenteric ganglia in the intestinal loops upstream from a sub-total stenosis induced by ligation of the rat gut and demonstrated that, together with smooth muscle hypetrophy, an increase in the size and number of ganglionic cell bodies of the Auerbach’s and Meissner’s plexuses was also evident. Few years later Filogamo and Vigliani (1953, 1954) repeated the Benninghoff experiment in dogs carrying on extensive statistical assessment of the correlation between the size of the innervation territory and the number of myenteric neurons. These in depth studies demonstrated that neuron hypertrophy is not the only feature of the adaptive process that occurs in the intestinal loops upstream from the partial obstruction. In fact, a significant increase of nerve cell number was also detected. Since there was no evidence of mitotic nerve cells, the observed increase in the number of neurons has been attributed to the persistence in the adult Auerbach’s plexus of poorly differentiated or undifferentiated cells capable of turning into neurons under the influence of exceptional stimuli. This process of cell recruitment leads to a four–five-fold increase in the number of differentiated neurons in the myenteric ganglia. Some of the newborn
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neurons also give rise to new small ganglia as demonstrated by a significant increase in the number of ganglia. The experimental induction of hypotrophy in the intestinal loops upstream from the stenosis by means of the Thiry–Vella method (i.e. the surgical exclusion of an intestinal tract from the transit connecting it to the abdominal wall) showed that a dramatic reduction of the functional stimulation to meynteric neurons, that have been previous hyperstimulated, leads to a relevant decrease in the cell body size but not in the number of neurons (Filogamo and Lievre, 1955). In support of the view that undifferentiated progenitor cells persist along adulthood in myneteric ganglia is the recent demonstration that nestin, an intermediate filament protein that is considered a specific marker of neural progenitor cell, is expressed in the postnatal myenteric plexus (Silva et al., 2000). In contrast to the above mentioned reports, it should be noted that the occurrence of adult neurogenesis in the autonomic nervous system has been denied by Gabella (1984) who failed to detect it even under conditions of enhanced functional stimulation. Finally, a more recent series of papers on the same experimental model have shown that unscheduled DNA synthesis (i.e. not followed by cell division) occurs in some myenteric neurons from the hypertrophic loops. In fact, while autoradiography after 3 H-thymidine administration and PCNA immuno-staining showed the presence DNA neosynthesis in myenteric neurons (Giacobini-Robecchi et al., 1985, 1988; Poncino et al., 1991; Corvetti et al., 2001) cytophotometry after Feulgen staining suggested that this neosynthesis not associated with cell division but with a hyperdiploid DNA content (Giacobini-Robecchi et al., 1988; Poncino et al., 1991). In addition, electrophoretic analysis of the total genomic DNA extracted from myenteric ganglia isolated from hypertrophic loops have shown the presence of extra-bands migrating below the high molecular weight DNA, suggesting that DNA amplification can be the mechanism of the observed unscheduled DNA synthesis (Giacobini-Robecchi et al., 1995). Another demonstration of the possibility that neuron addition takes place in the postnatal autonomic nervous system has been provided using an experimental model represented by the denervation of the gut by means of the benzalkonium chloride (BAC) (Sato et al., 1978; Sakata et al., 1979). Local application of BAC to an intestinal tract induces the selective destruction of about 90% of the neurons of the Auerbach’s plexus. After few weeks, a significant increase (two–five-fold) in the mean neuronal density in the small ganglia located along the mesenteric nerves can be detected (Cracco and Filogamo, 1993). It should be noted that the location of mesenteric nerves represents the migration pathway of the neural crest cells that colonize the gut during development. Similarly to what detected in the loops upstream from a partial obstruction, mitoses were not observed thus suggesting that neuronal addition along mesenteric nerves of BAC-treated animals is due to the late differentiation of a pool of neural-crest derived elements that persisted, as un-
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differentiated precursors, along the developmental migration pathway. Williams and Jew (1991) have proposed that the late differentiation of neural-crest-derived precursors can be triggered by diffusible factors originated from the intestinal wall treated by the BAC where profound degenerative and regenerative processes take place. The same can be true also in the case of neuronal addition occurring in the myenteric plexus of the loops upstream from a sub-total intestinal stenosis (Filogamo and Vigliani, 1953; Filogamo, 1987). The existence of diffusible factors that stimulate neuronal differentiation can be deduced also by the observation that the PC12 cells transplanted in the intestinal wall of BAC-treated animals rapidly give rise to long filaments and differentiate into mature neurons (Filogamo and Cracco, 1995). Further evidence on the postnatal histogenesis in enteric nervous system comes from clinical studies that have shown that intestinal inflammation induces an increase in the number of neurons in the myenteric ganglia (Storsteen et al., 1953; Davis et al., 1955). Sharkey and Parr (1996) have recently revised the literature on this issue asking a question on how there can be more enteric neurons if these cells are postmitotic? They give an answer to this question suggesting that, since cell division in adult neurons is unlikely, the possible explanation for neuron addition in adulthood is that there are precursors cells in myenteric ganglia capable of late proliferation into adult neurons (Sharkey and Parr, 1996). As regards other sites of the autonomic nervous system, experimental data are poor though, similarly to what happens to the myenteric nervous system, the presence of a compartment of reserve progenitors cells has been reported in sympathetic ganglia (Celestino da Costa, 1939; Picard and Chambost, 1953).
4. Discussion and conclusions The issue of adult neurogenesis is very much in the news (both scientific and popular) now and great hopes are arising from the public about the therapeutic potential of adult neural stem cells. Most of the interest has been directed to the CNS and only little attention has been paid to postnatal histogenesis in the PNS, an issue that, in our opinion, deserves much more research. We hope that the overview of the literature provided in this article support our viewpoint. In particular we would like to focus on a feature that is shared by both sensory and autonomic neurons and that can be important for the understanding of the basic mechanisms of adult neurogenesis in the PNS: all these neurons originate from neural crest cells that early migrated form the neural tube during development. Neural crest migratory cells also give rise to cell populations belonging to many other organs such as the heart (Farrel et al., 1999). Cardiac neural crest cells partecipate in the development of the cardiac outflow septation and pattering of the great arteries and in the formation of the cardiac conducting cells (Filogamo et al., 1990). It has been recently demonstrated by Kirby
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and co-workers that the absence of cardiac neural crest cells leads to primary myocardial disfunction (Farrel et al., 1999) and a clinical condition (DiGeorge syndrome) associated to defects in organs and tissues that depend on contributions by cell populations derived from neural crest has also been described in the human (Farrel et al., 1999). The experimental and clinical evidence briefly outlined along this article led us to tentatively advance a working hypothesis that draw together the various elements arising from more than one century of studies: we suggest that neural crest cells, besides driving the development of many different tissue and organs during development, can play a role also in the post-developmental period of animal life because some of the migratory elements persist as peripherical reserve pool of multipotent stem cells that can undergo a late differentiation into mature cells. The recruitment of this reserve pool, that probably undergo a progressive age-related exhaustion (Filogamo and Cracco, 1995), is stimulated by various physiological and pathological conditions in which new cells are needed. If this were true, it would be foreseen that the employment of neural-crest-derived cells can become a powerful therapeutic tool in the hands of the clinicians for treating various degenerative diseases affecting the peripheral nervous system.
Acknowledgements This work was supported by grants from the MURST/ MIUR.
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