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K Unsicker

Publications and source records attributed to K Unsicker.

At least 55 records · Page 3Linked to original sources
PubMed1999

Expression of a novel member of the TGF-beta superfamily, growth/differentiation factor-15/macrophage-inhibiting cytokine-1 (GDF-15/MIC-1) in adult rat tissues.

We have cloned a novel member of the transforming growth factor-beta (TGF-beta) superfamily from a human placental cDNA library. The sequence is identical to five very recently published sequences, of which only one (macrophage inhibitory cytokine-1, MIC-1) has been characterized in terms of function. In light of the present data demonstrating the wide distribution of the mRNA and putative multifunctionality, we propose to name this molecule growth/differentiation factor-15/MIC-1 (GDF-15/MIC-1). The deduced amino acid sequence reveals typical features of a secreted molecule. The epithelium of the choroid plexus is the only site in the adult brain expressing detectable levels of GDF-15/MIC-1 mRNA. Many epithelia of non-neural tissues including those of the prostate and intestinal mucosa, bronchi and bronchioli, secretory tubuli of the submandibular gland, and lactating mammary gland are prominent sites of GDF-15/MIC-1 synthesis. GDF-15/MIC-1 is also strongly expressed by macrophages in the adrenal gland. Thus, GDF-15/MIC-1, like many other members of the TGF-beta superfamily, is widely distributed in adult tissues, being most strongly expressed in epithelial cells and macrophages.

Animals↗
PubMed1999

Midbrain dopaminergic neurons are protected from radical induced damage by GDF-5 application. Short communication.

Embryonic day 14 rat midbrain cultures were kept for 7 days in vitro and then intoxicated with radical donors iron and sodium-nitroprusside for 24 h. Tyrosine-hydroxylase positive neurons in cultures which were additionally treated with growth/differentiation factor-5 (GDF-5) survived to a significantly higher percentage as compared to sister cultures without factor supplementation. Since the degeneration of TH positive cells is a key feature in Parkinson's disease, GDF-5 might be a putative therapeutical agent for this disorder.

Animals↗
PubMed1999

Regulation of the transmitter phenotype of rostral and caudal groups of cultured serotonergic raphe neurons.

We have studied the regulation of survival and serotonergic markers by neurotrophins and several trophically active cytokines in neurons cultured from the embryonic rat raphe region under defined conditions. At embryonic day 14, saturating concentrations of brain-derived neurotrophic factor, neurotrophin-3, neurotrophin-4 and basic fibroblast growth factor elicited a two- to 2.5-fold increase in numbers of tryptophan hydroxylase- and serotonin-immunoreactive neurons over a four-day culture period. Transforming growth factor beta-1 and glial cell line-derived neurotrophic factor were less potent, while fibroblast growth factor-5 was only marginally effective. Distinct responses to different factors were noted depending on embryonic age and regional origin of serotonergic neurons. Thus, brain-derived neurotrophic factor augmented numbers of tryptophan hydroxylase-positive neurons at embryonic day 16 by a factor of seven, but only 1.5- to two-fold when cultures were established from day 13 or 14 embryos. In cultures of rostral serotonergic groups (B4-B9), numbers of tryptophan hydroxylase-positive neurons decreased in the absence of factors, whereas numbers of tryptophan hydroxylase-immunoreactive neurons in cultures from caudal serotonergic groups (B1-B3) increased during a 12-day culture period. There was no evidence that serotonergic neurons undergo apoptosis (as visualized by terminal deoxynucleotidyl transferase dUTP nick end labeling) or proliferate (as visualized by 5-bromodeoxyuridine incorporation) in culture. Numbers of serotonergic neurons also increased when cultures were treated with a brief 24-h pulse of brain-derived neurotrophic factor, supporting the notion that changes in numbers of serotonergic neurons reflected alterations of phenotype rather than cell death or proliferation. The ability of cells to specifically take up the serotonin analog 5,7-dihydroxytryptamine was also up-regulated by brain-derived neurotrophic factor in both rostral and caudal raphe cultures. Lability of the serotonergic phenotype was further suggested by the observation that ciliary neurotrophic factor fully prevented the brain-derived neurotrophic factor-mediated increase in tryptophan hydroxylase-positive neurons. The effect of ciliary neurotrophic factor was dependent on the presence of astrocytes. We conclude that serotonergic neurons show spatially and temporally distinct responses to neurotrophic factors, which seem to have a profound influence of the transmitter phenotype rather than on survival.

5,7-Dihydroxytryptamine↗
PubMed1999

Transforming growth factor-beta, but not ciliary neurotrophic factor, inhibits DNA synthesis of adrenal medullary cells in vitro.

Transforming growth factor-betas are members of a superfamily of multifunctional cytokines regulating cell growth and differentiation. Their functions in neural and endocrine cells are not well understood. We show here that transforming growth factor-betas are synthesized, stored and released by the neuroendocrine chromaffin cells, which also express the transforming growth factor-beta receptor type II. In contrast to the developmentally related sympathetic neurons, chromaffin cells continue to proliferate throughout postnatal life. Using 5-bromo-2'-deoxyuridine pulse labeling and tyrosine hydroxylase immunocytochemistry as a marker for young postnatal rat chromaffin cells, we show that treatment with fibroblast growth factor-2 (1 nM) and insulin-like growth factor-II (10 nM) increased the fraction of 5-bromo-2'-deoxyuridine-labeled nuclei from 1% to about 40% of the cells in the absence of serum. In the presence of fibroblast growth factor-2 and insulin-like growth factor-II, transforming growth factor-beta1 (0.08 nM) reduced 5-bromo-2'-deoxyuridine labeling by about 50%, without interfering with chromaffin cell survival or death. Doses lower and higher than 0.08 nM were less effective. Similar effects were seen with transforming growth factor-beta3. In contrast to transforming growth factor-beta, ciliary neurotrophic factor, which inhibits proliferation of sympathetic progenitor cells, was not effective on rat chromaffin cells from postnatal day 6. Glucocorticoids also suppress DNA synthesis in fibroblast growth factor-2/insulin-like growth factor-II-treated chromaffin cells. This effect was not mediated by chromaffin cell-derived transforming growth factor-beta, as shown by addition of neutralizing antibodies. We conclude that one function of adrenal medullary transforming growth factor-beta may be to act as a negative regulator of chromaffin cell division.

Adrenal Medulla↗
PubMed1999

Characterization of bone morphogenetic protein family members as neurotrophic factors for cultured sensory neurons.

The bone morphogenetic proteins have been implicated in several inductive processes throughout vertebrate development including nervous system patterning. Recently, these proteins have also emerged as candidates for regulating survival of mesencephalic dopaminergic and sympathetic neurons. Interestingly, we have found that several bone morphogenetic proteins can be detected in developing embryonic day 14 rat dorsal root ganglia by means of reverse transcription-polymerase chain reaction and immunocytochemistry. To further elucidate their potential role during the period of ontogenetic neuron death, serum-free cultures of dorsal root sensory neurons from developing chick and rat embryos were treated with distinct bone morphogenetic proteins with or without simultaneous addition of other "established" neurotrophic factors. Our results show that bone morphogenetic proteins exert survival promoting effects on their own, and that they can positively modulate the effects of neurotrophins on sensory neurons. In particular, growth/differentiation factor-5, bone morphogenetic protein-2, -4, -7 and -12 significantly increased the survival promoting effects of neurotrophin-3 and nerve growth factor on cultured dorsal root ganglion neurons. These results fit well into the current concept that neurotrophic factors may act synergistically in ensuring neuronal survival. Moreover, these data suggest potential instructive interactions of bone morphogentic proteins and neurotrophins during sensory neuron development. Finally, the documented neurotrophic capacity of bone morphogenetic protein family members may have potential relevance for the treatment of peripheral neuropathies.

Animals↗
PubMed1999

Essential role for TrkB receptors in hippocampus-mediated learning.

Brain-derived neurotrophic factor (BDNF) and its receptor TrkB regulate both short-term synaptic functions and long-term potentiation (LTP) of brain synapses, raising the possibility that BDNF/TrkB may be involved in cognitive functions. We have generated conditionally gene targeted mice in which the knockout of the trkB gene is restricted to the forebrain and occurs only during postnatal development. Adult mutant mice show increasingly impaired learning behavior or inappropriate coping responses when facing complex and/or stressful learning paradigms but succeed in simple passive avoidance learning. Homozygous mutants show impaired LTP at CA1 hippocampal synapses. Interestingly, heterozygotes show a partial but substantial reduction of LTP but appear behaviorally normal. Thus, CA1 LTP may need to be reduced below a certain threshold before behavioral defects become apparent.

Animals↗
PubMed1999

Differential regulation of distinct phenotypic features of serotonergic neurons by bone morphogenetic proteins.

Bone morphogenetic proteins (BMPs), growth and differentiation factor 5 (GDF5) and glial cell line-derived neurotrophic factor (GDNF) are members of the transforming growth factor-beta superfamily that have been implicated in tissue growth and differentiation. Several BMPs are expressed in embryonic and adult brain. We show now that BMP-2, -6 and -7 and GDF5 are expressed in the embryonic rat hindbrain raphe. To start to define roles for BMPs in the regulation of serotonergic (5-HT) neuron development, we have generated serum-free cultures of 5-HT neurons isolated from the embryonic (E14) rat raphe. Addition of saturating concentrations (10 ng/mL) of BMP-6 and GDF5 augmented numbers of tryptophan hydroxylase (TpOH) -immunoreactive neurons and cells specifically taking up 5, 7-dihydroxytryptamine (5,7-DHT) by about two-fold. Alterations in 5-HT neuron numbers were due to the induction of serotonergic markers rather than increased survival, as shown by the efficacy of short-term treatments. Importantly, BMP-7 selectively induced 5, 7-DHT uptake without affecting TpOH immunoreactivity. BMP-6 and -7 also promoted DNA synthesis and increased numbers of cells immunoreactive for vimentin and glial fibrillary acidic protein (GFAP). Pharmacological suppression of cell proliferation or glial development abolished the induction of serotonergic markers by BMP-6 and -7, suggesting that BMPs act indirectly by stimulating synthesis or release of glial-derived serotonergic differentiation factors. Receptor bodies for the neurotrophin receptor trkB, but not trkC, abolished the BMP-mediated effects on serotonergic development, suggesting that the glia-derived factor is probably brain-derived neurotrophic factor (BDNF) or neurotrophin-4. In support of this notion, we detected increased levels of BDNF mRNA in BMP-treated cultures. Together, these data suggest both distinct and overlapping roles of several BMPs in regulating 5-HT neuron development.

5,7-Dihydroxytryptamine↗
PubMed1999

Analysis of mice carrying targeted mutations of the glucocorticoid receptor gene argues against an essential role of glucocorticoid signalling for generating adrenal chromaffin cells.

Molecular mechanisms underlying the generation of distinct cell phenotypes is a key issue in developmental biology. A major paradigm of determination of neural cell fate concerns the development of sympathetic neurones and neuroendocrine chromaffin cells from a common sympathoadrenal (SA) progenitor cell. Two decades of in vitro experiments have suggested an essential role of glucocorticoid receptor (GR)-mediated signalling in generating chromaffin cells. Targeted mutation of the GR should consequently abolish chromaffin cells. The present analysis of mice lacking GR gene product demonstrates that animals have normal numbers of adrenal chromaffin cells. Moreover, there are no differences in terms of apoptosis and proliferation or in expression of several markers (e.g. GAP43, acetylcholinesterase, adhesion molecule L1) of chromaffin cells in GR-deficient and wild-type mice. However, GR mutant mice lack the adrenaline-synthesizing enzyme PNMT and secretogranin II. Chromaffin cells of GR-deficient mice exhibit the typical ultrastructural features of this cell phenotype, including the large chromaffin granules that distinguish them from sympathetic neurones. Peripherin, an intermediate filament of sympathetic neurones, is undetectable in chromaffin cells of GR mutants. Finally, when stimulated with nerve growth factor in vitro, identical proportions of chromaffin cells from GR-deficient and wild-type mice extend neuritic processes. We conclude that important phenotypic features of chromaffin cells that distinguish them from sympathetic neurones develop normally in the absence of GR-mediated signalling. Most importantly, chromaffin cells in GR-deficient mice do not convert to a neuronal phenotype. These data strongly suggest that the dogma of an essential role of glucocorticoid signalling for the development of chromaffin cells must be abandoned.

Adrenal Glands↗
PubMed1998

Gap junction uncoupling of neonatal rat astroglial cultures does not affect their expression of fibroblast growth factor 2.

Fibroblast growth factor (FGF)-2 is expressed by astroglial cells and regulates astroglial proliferation, differentiation, and gap junction communication. We show now that uncoupling of astroglial cells cultured from neonatal rat cortex, striatum and mesencephalon by 18alpha-glycirrhetinic acid (AGA) or arachidonic acid (AA) (demonstrated by intracellular injections of Lucifer Yellow) does affect neither levels of FGF-2 mRNA (investigated by a competitive RT-PCR method), nor protein (as revealed by Western blot analysis). This suggests that expression of FGF-2, which reduces gap junction communication of cortical and striatal astroglial cells [15], is not affected when astroglial cells are uncoupled. Regulation of FGF-2 expression and coupling in astroglial cells are thus not reciprocal suggesting more complex interrelationships between these two important parameters of astroglial cell differentiation.

Animals↗
PubMed1998

Glial cell line-derived neurotrophic factor requires transforming growth factor-beta for exerting its full neurotrophic potential on peripheral and CNS neurons.

Numerous studies have suggested that glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic molecule. We show now on a variety of cultured neurons including peripheral autonomic, sensory, and CNS dopaminergic neurons that GDNF is not trophically active unless supplemented with TGF-beta. Immunoneutralization of endogenous TGF-beta provided by serum or TGF-beta-secreting cells, as e.g., neurons, in culture abolishes the neurotrophic effect of GDNF. The dose-response relationship required for the synergistic effect of GDNF and TGF-beta identifies 60 pg/ml of either factor combined with 2 ng/ml of the other factor as the EC50. GDNF/TGF-beta signaling employs activation of phosphatidylinositol-3 (PI-3) kinase as an intermediate step as shown by the effect of the specific PI-3 kinase inhibitor wortmannin. The synergistic action of GDNF and TGF-beta involves protection of glycosylphosphatidylinositol (GPI)-linked receptors as shown by the restoration of their trophic effects after phosphatidylinositol-specific phospholipase C-mediated hydrolysis of GPI-anchored GDNF family receptor alpha. The biological significance of the trophic synergism of GDNF and TGF-beta is underscored by colocalization of the receptors for TGF-beta and GDNF on all investigated GDNF-responsive neuron populations in vivo. Moreover, the in vivo relevance of the TGF-beta/GDNF synergism is highlighted by the co-storage of TGF-beta and GDNF in secretory vesicles of a model neuron, the chromaffin cell, and their activity-dependent release. Our results broaden the definition of a neurotrophic factor by incorporating the possibility that two factors that lack a neurotrophic activity when acting separately become neurotrophic when acting in concert. Moreover, our data may have a substantial impact on the treatment of neurodegenerative diseases.

Androstadienes↗
PubMed1998

TrkB and neurotrophin-4 are important for development and maintenance of sympathetic preganglionic neurons innervating the adrenal medulla.

The adrenal medulla receives its major presynaptic input from sympathetic preganglionic neurons that are located in the intermediolateral (IML) column of the thoracic spinal cord. The neurotrophic factor concept would predict that these IML neurons receive trophic support from chromaffin cells in the adrenal medulla. We show here that adrenal chromaffin cells in the adult rat store neurotrophin (NT)-4, but do not synthesize or store detectable levels of BDNF or NT-3, respectively. Preganglionic neurons to the adrenal medulla identified by retrograde tracing with fast blue or Fluoro-Gold (FG) express TrkB mRNA. After unilateral destruction of the adrenal medulla, 24% of IML neurons, i.e., all neurons that are preganglionic to the adrenal medulla in spinal cord segments T7-T10, disappear. Administration of NT-4 in gelfoams (6 microgram) implanted into the medullectomized adrenal gland rescued all preganglionic neurons as evidenced by their presence after 4 weeks. NT-3 and cytochrome C were not effective. The action of NT-4 is accompanied by massive sprouting of axons in the vicinity of the NT-4 source as monitored by staining for acetylcholinesterase and synaptophysin immunoreactivity, suggesting that NT-4 may enlarge the terminal field of preganglionic nerves and enhance their access to trophic factors. Analysis of TrkB-deficient mice revealed degenerative changes in axon terminals on chromaffin cells. Furthermore, numbers of FG-labeled IML neurons in spinal cord segments T7-T10 of NT-4-deficient adult mice were significantly reduced. These data are consistent with the notion that NT-4 from chromaffin cells operates through TrkB receptors to regulate development and maintenance of the preganglionic innervation of the adrenal medulla.

Adrenal Medulla↗
PubMed1998

GDNF-related factor persephin is widely distributed throughout the nervous system.

Persephin (PSP) is the most recently discovered member of the GDNF family of neurotrophic factors. We have used an RT-PCR approach to start addressing the putative functional significance of PSP by determining sites of its synthesis in the neonatal rat brain. Generally, two transcripts were found. Sequence analysis of the transcripts identifies an 88 bp intronic sequence. Neural tissues analysed included cortex, hippocampus, striatum, diencephalon, mesencephalon, cerebellum, hindbrain and spinal cord as well as superior cervical, dorsal root ganglia, adrenal gland, and PC12 pheochromocytoma cells. As non-neuronal tissues, sciatic nerve, optic nerve, primary astroglial, oligodendroglial, O2A progenitor, and glioma cells (C6, B49) were also included. All tissues/cells except oligodendrocytes and O2A progenitor cells were strongly positive for PSP mRNA. To test the hypothesis of whether PSP might act as a target-derived factor, as suggested for GDNF, the motoneuron-muscle axis has been analysed. PSP is synthesized in skeletal muscle and, to a higher extent, in the spinal cord. Moreover, PSP is synthesized in purified embryonic motoneurons. Together, these data do not support a role for PSP as a typical target-derived neurotrophic factor for motoneurons. We conclude that PSP is synthesized throughout the nervous system and that it is presumably of both astroglial and neuronal origin, in contrast to GDNF and neurturin, which seem to be predominantly of neuronal origin.

Adrenal Gland Neoplasms↗
PubMed1998

Distinct populations of macrophages in the adult rat adrenal gland: a subpopulation with neurotrophin-4-like immunoreactivity.

Macrophages are widely distributed in lymphohaemopoietic and many other mammalian tissues, where they are mainly involved in host defence mechanisms, phagocytosis, wound repair, and secretion of growth factors. Increasing evidence suggests that secretory products of macrophages can influence adrenal gland functions. In the present study, we have used specific antibodies to ED1 (cytoplasmic antigen), ED2 (membrane antigen), ED8 (membrane antigen), and OX-6 (MHC class II/membrane antigen) as markers for macrophages to examine their distribution within the adult rat adrenal gland. ED2 and OX-6 recognize distinct subpopulations of adrenal gland macrophages, whereas macrophages immunoreactive (-ir) for ED1 and ED8 could not be detected. OX-6-ir macrophages were most numerous in the cortical reticularis and glomerulosa zones, while only few cells were found in the zona fasciculata and in the adrenal medulla. Macrophages immunoreactive for ED2 were restricted to the adrenal medulla. The majority of these macrophages were associated with vascular sinuses or chromaffin cells. By double-immunolabelling we found that most of ED2-ir medullary macrophages contain neurotrophin-4 (NT-4)-like ir. Attempts to clarify whether macrophages take up NT-4 from NT-4-ir chromaffin cells indicated that medullary macrophages are immunonegative for chromogranin A and neuropeptide Y, two major secretory products of chromaffin cells. In situ hybridizations and immunofluorescence showed expression of the neurotrophin receptor TrkA, but not TrkB in the adrenal medulla. In vitro studies indicated that NT-4, similar to nerve growth factor, can induce c-fos-ir in chromaffin cells. We conclude that chromaffin cells are putative targets for adrenal medullary NT-4, whose functions remain to be clarified.

Adrenal Cortex↗
PubMed1998

Calcitonin gene-related peptide promotes differentiation, but not survival, of rat mesencephalic dopaminergic neurons in vitro.

The aim of this study was to investigate putative effects of calcitonin gene-related peptide on developing dopaminergic neurons in the ventral mesencephalon. To determine a time-point for a physiological role of calcitonin gene-related peptide in the development of this system, we first investigated calcitonin gene-related peptide messenger RNA expression in the ventral mesencephalon of Wistar rats at embryonic days (E) 11-19. Calcitonin gene-related peptide messenger RNA was not detectable at E11, i.e. prior to the appearance of dopaminergic neurons in this area. From E14 to E19, calcitonin gene-related peptide messenger RNA was expressed in increasing amounts. We therefore investigated the effects of calcitonin gene-related peptide on serum-free cell cultures established from the E14 midbrain floor. Addition of calcitonin gene-related peptide (200 ng/ml) every other day significantly increased neuronal differentiation, including longer tyrosine hydroxylase-positive neurites, enhanced immunoreactivity for growth-associated protein-43 and increased dopaminergic uptake per neuron. These effects were maximal after seven to eight days. Calcitonin gene-related peptide acted synergistically with fibroblast growth factor-2 on these parameters. In contrast to fibroblast growth factor-2, however, calcitonin gene-related peptide did not promote survival of tyrosine hydroxylase-immunoreactive neurons. Lack of calcitonin gene-related peptide expression in the mesencephalon at E11 was paralleled by a lack of effect of calcitonin gene-related peptide on early presumptive dopaminergic neurons in terms of eliciting this phenotype. Our data suggest that calcitonin gene-related peptide may act physiologically as a differentiation-promoting factor for phenotypically defined dopaminergic neurons during a time period when dopaminergic neurons assemble in the ventral mesencephalon and grow axons towards their targets.

Animals↗
PubMed1998

Fibroblast growth factor 2 (FGF-2) differentially regulates connexin (cx) 43 expression and function in astroglial cells from distinct brain regions.

Fibroblast growth factor (FGF)-2 is a peptide growth factor that promotes the generation, differentiation, and survival of neurons and glial cells. In the CNS, astroglial cells are coupled in a region-specific manner by gap junctions consisting of connexin 43 (cx43). In the present study we have investigated effects of FGF-2 and of other growth factors on the expression and function of cx43 in astroglial cells cultured from telencephalic cortex, striatum, and mesencephalon of newborn rats. Confluent cultures were maintained for two days in low serum, and then exposed to FGF-2 (10 ng/ml) for 48 h. FGF-2 caused a reduction of cx43-protein, -mRNA, and intercellular communication revealed by dye spreading. These changes occurred in cortical and striatal cells, but not in mesencephalic astroglial cells. Effects of FGF-2 were time- and concentration-dependent, with a minimal effective dose of 1 ng/ml FGF-2, and an onset of effects after 6 h of incubation. The reduction of coupling by FGF-2 was transient, since in cortical and striatal cultures coupling recovered to control levels 48 h after removal of the growth factor. Like FGF-2, transforming growth factor-beta3 (TGF-beta3) decreased coupling of cortical and striatal, but not mesencephalic astroglial cells. Astroglial cells from all brain regions showed a slight FGF-mediated increase in 5-bromo-2'-desoxy-uridine (BrdU) incorporation, which was abolished upon co-treatment with TGF-beta3. However, TGF-beta3 did not interfere with the repression of cx43-function by FGF-2. Epidermal growth factor (EGF) that has been demonstrated to influence coupling in other cell types had no effect on dye spreading but significantly increased BrdU incorporation. Our results reveal a novel function of FGF-2 on cultured astroglial cells which may be relevant to the regulation of astroglial cell connectivity in vivo.

Animals↗
PubMed1998

Regulation of gap junction communication by growth factors from non-neural cells to astroglia: a brief review.

Astrocytes are coupled by gap junctions, which are composed of connexins, channel-forming proteins. Connexin43 is the predominant connexin of astrocytes. Gap junctions assemble astrocytes into functional syncytia permitting exchange of small molecules including metabolites, catabolites, and second messenger molecules. Thus, gap junctions of astroglial cells serve the maintenance of extra- and intra-cellular homeostasis in the brain and eventually ascertain neuronal functions. Alterations in astroglial cell coupling can disturb this equilibrium resulting in neuronal dysfunction and death. Growth factors are an important class of substances that can influence coupling in non-neural cells. Several groups have recently carried the analyses of gap junction regulation by cytokines to the level of neural cells. This review summarizes the recent progress in this field and outlines directions of future research.

Animals↗
PubMed1998

Short communication: transforming growth factor-beta mediates the neurotrophic effect of fibroblast growth factor-2 on midbrain dopaminergic neurons.

Fibroblast growth factor (FGF)-2 is an established neurotrophic factor for dopaminergic (DAergic) neurons in the ventral midbrain. Its survival and differentiation-promoting effects on DAergic neurons in vitro and in vivo are crucially dependent on the presence, numerical expansion and maturation of astroglial cells. We show now that transforming growth factor (TGF)-beta, an established trophic factor for DAergic neurons and product of astroglial cells, mediates the trophic effect of FGF-2 on DAergic neurons cultured from the embryonic rat midbrain floor. Antibodies to TGF-beta that neutralize the isoforms -beta1, -beta2 and -beta3 abolish the trophic effect of FGF-2. FGF-2 increases TGF-beta3 mRNA and amounts of biologically active TGF-beta determined in a mink lung epithelial cell assay in a time-dependent manner. FGF-2 also induces levels of active TGF-beta in neonatal rat astrocytes cultured from midbrain, striatum and cortex. We conclude that TGF-beta is required for mediating the survival promoting effect of FGF-2 on DAergic and, possibly, cortical and striatal neurons grown in the presence of glial cells.

Animals↗