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From the Laboratoire d'Histologie-Embryologie et Service
d'Anatomie Pathologique,*
Laboratoire de Greffe de
Moelle,
Université Victor Segalen,
Bordeaux, and the Service des Maladies du
Sang,
Hôpital Haut-Lévêque,
Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Truncated receptors lacking the kinase domain (TK-) have been described for TrkB and TrkC but not for TrkA.15-18 These receptors may function as dominant negative isoforms or immunoadhesins.13,19,20 Both TK+ and TK- receptors have been detected in neurons while only truncated TrkB and TrkC isoforms have been detected primarily in nonneuronal cells.15-18,21
The expression of functional NGF receptors has been detected in several bone marrow-derived cells such as monocytes,22 mastocytes,23,24 and B or T cell clones.25-28 Among its pleiotropic effects, NGF induces platelet shape changes,29 triggers monocyte cytotoxic activity,22 and induces basophilic cell differentiation30-32 and mast cell development and degranulation.24,33 However, NGF receptors have not been consistently detected on bone marrow cells. Although trkA and p75LNGFR transcripts have been detected in long-term bone marrow cultures,34,35 trkA transcripts were not always found within fresh bone marrow aspirates.35,36 NGF transcripts have not been detected in human bone marrow.35 The local expression of other NT genes has not been investigated.
The expression of NT receptors in human fetal and adult bone marrow was investigated by immunocytochemistry and by reverse transcription-polymerase chain reaction (RT-PCR). Several sets of primers were designed to detect transcripts encoding for catalytic or truncated isoforms of the Trk family receptors. We also studied the local expression of all NT genes. Our data suggest that all NT are synthesized within the bone marrow in a developmentally regulated fashion. Their corresponding transducing or truncated receptors were detected on specific hematopoietic cells and on stromal cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Four groups of patients were investigated: fetuses (n = 4) of 16, 23, 25, and 32 weeks fetal age, adults with reactive bone marrow (n = 7), neoplasm-bearing adult patients without bone marrow hematopoietic involvement (n = 15) (Hodgkin's disease, n = 4; non-Hodgkin's lymphoma, n = 7; mycosis fungoides, n = 1; treated acute leukemia, n = 1; lung carcinoma, n = 1; thymoma, n = 1), and patients presenting with reactive mastocytosis (n = 3). Bone marrow trephine biopsies were obtained with a Jamshidy needle. Fetal necropsy tissues consisted of rib cage samples. In all cases, fresh bone marrow samples were either snap-frozen in liquid nitrogen-precooled isopentane and stored at -80°C or fixed in Bouin's fixative. Bone marrow smears were obtained from fetuses (n = 4) and adult patients without hematological disorders (n = 22), air-dried, and acetone-fixed for 10 minutes at 20°C. Bone marrow tissues were decalcified by electrolysis in decalcifying buffer (Bayer Diagnostics, Puteaux, France) for 2 hours and embedded in paraffin.
Immunocytochemistry
Antibodies
Two monoclonal anti-human nerve growth factor receptor (p75LNGFR) antibodies, clone 8211 (Boehringer Mannheim, Mannheim, Germany) labeling both ECDs and intracellular domains, and clone NGFR5 (Dako, Copenhagen, Denmark) directed against the ECD of the receptor, were used to study p75LNGFR immunoreactivity (IR). The polyclonal antibodies Trk (C-14), TrkA (763), TrkB (794), TrkB(TK-) (C-13), TrkC (798) (all Santa Cruz Biotechnology, Santa Cruz, CA), r-TrkA (gift of Dr. L. F. Reichardt), anti-TrkB In pAb (Promega, Madison, WI), and TrkC NC2 (gift of Dr. F. Lamballe) were used to study Trk family receptors. Trk (C-14) is broadly reactive with an epitope corresponding to amino acids 777–790 of the conserved carboxy terminus of TrkA and cross-reacts with TrkB and TrkC receptors. TrkA (763) reacts against a carboxy terminal epitope of human TrkA (amino acids 763–777). TrkB (794) and TrkC (798) were raised against carboxy terminal peptides (794–808 and 798–812 residues respectively) of gp145TrkB or gp145TrkC proteins. TrkB(TK-) (C-13) reacts with an epitope mapping at the carboxy terminus of the truncated (TK-) TrkB protein. r-TrkA is directed against a rat TrkA ectodomain.37 TrkB In pAb is raised in chickens against a mouse TrkB intracellular domain corresponding to amino acids 482–501. The anti-TrkC NC2 is directed against a peptide corresponding to the exon B of the rat TrkC TK- receptors ic158 and ic143.15
Methods
Bone marrow smears were incubated for 1 hour at room temperature in Tris-buffered saline 0.05 mol/L, pH 7.6, 10% BSA with TrkA (763) (1/100), r-TrkA (1/100), TrkB (794) (1/50), TrkB (C-13) (1/100), TrkB In pAb (1/100), TrkC798 (1/100), TrkC NC2 (1/200), or anti-p75LNGFR (clone 8211) (1/150). For monoclonal p75LNGFR antibodies, the slides were incubated directly with a rabbit anti-mouse alkaline anti-alkaline phosphatase (APAAP) complex, then revealed with Nitro blue-bromochloroindolyphosphate phosphatase substrate. For rabbit polyclonal antibodies, an incubation with a mouse anti-rabbit antibody (Dako) was performed before APAAP staining. For the chicken anti-TrkB In pAb, a rabbit anti-chicken IgY HRP conjugate (Promega) was used at a dilution of 1/100 followed by the mouse anti-rabbit step.
For fixed tissues, 5-µm sections were dried overnight at 37°C on SuperFrost/Plus glass slides (Menzel-Glaser, Braunschweig, Germany), deparaffinized in xylol, and brought to water through a graded alcohol series. Sections were then pretreated in a microwave oven in a 0.01 mol/L (pH 6.0) citrate buffer for 15 minutes. Endogenous peroxidase activity was inhibited with 1% H2O2-methanol for 5 minutes. Primary antibodies diluted in phosphate-buffered saline (Trk (C14) (1/300), TrkA (763) (1/1500), TrkB (794) (1/500), TrkB (C-13) (1/300), TrkC (798) (1/300), r-TrkA (1/750), TrkB In pAb (1/300), TrkC NC2 (1/200), p75LNGFR (1/1000)) were applied overnight on tissue sections. Immunodetection was performed with the biotin-streptavidin-peroxidase LSAB kit (Dako) for rabbit anti-Trks antibodies with an additional rabbit anti-chicken antibody for TrkB In pAb. A catalyzed signal amplification system (Dako) was also used with the monoclonal anti-p75LNGFR antibodies. Sections were counterstained by hematein or slow Giemsa.
Frozen and paraffin-embedded fixed human and rat forebrains were processed as positive controls. For TrkA (763), TrkB (794), and TrkC (798), specific controls were performed on adjacent slides, either by omitting the primary or secondary antibody or by coincubation with either the corresponding homologous control peptide or the heterologous control peptide (Santa Cruz Biotechnology) as previously reported.38,39 Trk (C-14), TrkA (763), TrkB (794), and TrkC (798) IR were not altered by coincubation with the heterologous peptides and the Trk homologous peptide specifically abolished the signal.
To confirm the IR of each Trk, the stainings with antibodies reacting with different regions of each Trk receptor were compared, ie, Trk (C-14), TrkA (763), and r-TrkA for TrkA; Trk (C-14), anti-TrkB In pAb, and TrkB (794) for kinase TrkB; and Trk (C-14) and TrkC (798) for kinase TrkC. Trk-immunoreactive cells were identified on the basis of morphological criteria and, in some instances, immunohistochemistry was performed on adjacent sections with one of the following antibodies: anti-vimentin, BNH9, -PS100, or -CD68 (KP-1) (Dako).
RT-PCR
RNA was extracted from frozen adult (n = 7)
and fetal (n = 3, range, 16–25 weeks fetal age)
bone marrow by using Trizol reagent (Gibco BRL, Gaithersburg, MD).
Forty units of DNaseI (Boehringer Mannheim) were used per µg of RNA
to remove potential genomic DNA contamination. Reverse transcription
was performed for 1 hour at 37°C with 10 µg of total RNA using
random hexamers (pd(N)6; Boehringer Mannheim), 50 mmol/L Tris-HCl, pH
8.3, 75 mmol/L KCl, 3 mmol/L MgCl2, 500 µmol/L
of each deoxynucleotide-5'-triphosphate and 400 U of superscript II RT
(Gibco BRL) in a final volume of 40 µl. The reverse transcription
step and the relative homogeneity of the cDNA concentration were
controlled by amplifying the ubiquitously expressed Abl transcript with
primers AblA2 5' and 3'. For each PCR, cDNA corresponding to 0.8 µg
of total RNA was amplified with primers (Table 1
and Figure 1
) designed to investigate the expression
of NT and trk isoform transcripts. PCR was performed in 10
mmol/L Tris-HCl, pH 9, 50 mmol/L KCl, 1.5 mmol/L
MgCl2, 200 µmol/L of each
deoxynucleotide-5'-triphosphate, 0.1% Triton X-100, with 50 pmol of
each primer and 1.5 U of Taq polymerase (Promega) in a final
volume of 50 µl. A 4-minute denaturation step at 94°C was followed
by 36 cycles of 94°C for 1 minute, 64°C (TrkC Kin 5'-3') or 62°C
(TrkC ECD 5'-3') or 60°C (TrkA ECD 5'-3', TrkB ECD 5'-3', TrkB Kin
5'-3', TrkB Trunc 5'-3', TrkC Trunc 5'-3', NGF 5'-3', BDNF 5'-3',
NT3 5'-3', NT4 5'-3', AblA2 5'-3') for 1 minute, 72°C for 1
minute, and a final extension at 72°C for 10 minutes in an automated
thermal cycler (Hybaid, Teddington, UK). To ensure the absence of
residual DNA contamination, 0.8 µg of each RNA were amplified using
the 5' and 3' BDNF primers without the reverse transcription step. Ten
µl of each reaction were run onto a 2.5% agarose gel. Negative
(reaction mixture without DNA template) and positive (cDNA from human
caudate putamen) controls were included in each PCR set.
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For each primer set, RT-PCR products from one adult bone marrow and from the human caudate putamen cDNA were submitted to nucleotide sequencing analysis. Briefly, PCR products were run onto a 10% acrylamide gel and the bands were excised and PCR-amplified using the appropriate set of primers as previously described. PCR products were purified through MicroSpin S300 Columns (Pharmacia Biotechnology, Uppsala, Sweden), then sequenced in both DNA strands using the ABI PRISM Dye Terminator Cycle Sequencing Ready Reaction Kit (Perkin Elmer Applied Biosystems, Foster City, CA) on an automated Applied ABI 377A DNA sequencer (Perkin Elmer). Nucleotide sequence data were analyzed using the Sequence Navigator Software (Perkin Elmer) and a sequence comparison was made with the GenBank database using the Wisconsin Package (Genetics Computer Group, Madison, WI).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We investigated the immunolocalization of
p75LNGFR and Trk receptors in vivo in
fetal and adult human hematopoietic tissues. Immunostaining of bone
marrow smears or sections produced comparable results, allowing precise
identification of cells immunoreactive for the different NT receptors
according to their distribution and cytomorphology (Figures 2 and 3
, Table 2
).
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, in the endo-osteal surface of
bone trabeculae, or in bone marrow parenchyma in contact with
hematopoietic cells. The p75LNGFR-positive ARC
had an oval nucleus, a triangular cytoplasm, and long, thin, branching
dendrites better seen on bone marrow smears (Figures 2H and 3)
.
Pan-Trk IR, detected with the TrkA (C-14) antibody, overlapped with IR
for each TrkA, TrkB, or TrkC catalytic receptor. In adult bone marrow,
IR for a given receptor was observed on specific hematopoietic cell
types depending on their maturation stage (Figures 2 and 3)
. In
erythroblastic islets, an intense cytoplasmic or membranous TrkA IR was
seen on proerythroblasts and erythroblasts, whereas mature cells with a
pycnotic nucleus were stained either weakly or not at all (Figure 2, A
-D). A weak cytoplasmic TrkA IR was also seen in some macrophages
(data not shown), and in a subset of ARC and plasma cells (Figure 2G)
.
A cytoplasmic staining for the TrkB TK+ receptor
was found on mature eosinophilic metamyelocytes and polymorphonuclear
cells (data not shown), but not on immature eosinophilic cells or on
neutrophilic or basophilic cells. Some plasmocytes and a few
macrophages also showed a membranous and/or cytoplasmic TrkB
TK+ IR (data not shown). Membranous and
cytoplasmic staining for the truncated TrkB receptor was noted in all
erythroblasts and megacaryocytes (Figures 2E and 3)
. Cytoplasmic
staining for the TrkC TK+ receptor was found on
promyelocytes, myelocytes, metamyelocytes, and polymorphonuclear cells,
both in the neutrophilic and eosinophilic lineages and on
megacaryocytes (Figure 2F)
. This staining was also observed on a subset
of ARC and macrophages, whereas plasma cells had a membranous staining
for TrkC. Interestingly, the staining for truncated
TrkC TK- receptor was observed on the same
cellular subsets showing TrkC TK+ IR on both bone
marrow sections and smears. In reactive mastocytosis, for mast cells
there was weak staining for TrkA and intense cytoplasmic staining for
TrkB TK+, TrkC TK+, and
truncated TrkB and TrkC (data not shown).
At early fetal stages (16, 23, and 25 weeks), the p75LNGFR-positive cells also formed a network spreading from the vessel adventitial layer into the bone marrow parenchyma (data not shown). Trk IR was weak or absent in a few hematopoietic cells with a similar pattern to adult bone marrow consisting in TrkA IR in erythroblasts, TrkB TK+ IR in eosinophils, TrkB TK- IR in erythroblasts and megacaryocytes and TrkC TK+ and TK- IR in megacaryocytes but not in myelocytes (data not shown). On these fetal bone marrow sections, osteoblasts were intensely stained for TrkB TK+ and osteoclasts were sometimes stained for TrkA and TrkC (data not shown). At 32 weeks fetal age, the bone marrow was hypercellular and the IR for each receptor was similar to the IR in adult samples.
RT-PCR Detection of Neurotrophins and their Receptor Transcripts
The RT-PCR study was performed to identify transcripts encoding
for the different isoforms of the Trk family receptors, as summarized
in Figure 1
according to Shelton et al.13 The specificity of
each fragment was checked both by electrophoresis and by sequencing.
The expression pattern of Trk receptor transcripts was found to be
similar in adult and fetal bone marrow. All transcripts identified in
human central nervous system13
were also detected
in human bone marrow, except for the TrkAII isoform. Interestingly, the
TrkA ECD primer set amplified a 229-bp fragment corresponding to the
TrkAI isoform in human bone marrow, whereas the 247-bp fragment
corresponding to the TrkAII-spliced variant was detected only in the
human caudate putamen control (Figures 4 and 5)
. The TrkB primer sets amplified a
571-bp fragment coding for the kinase domain, a 245-bp fragment for the
ECD, and a 161-bp fragment corresponding to the truncated TrkB T1
isoform.
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. The sequence of
the 204-bp trkC transcript was slightly different from that previously
reported for human tissue.13
In both bone marrow
and central nervous system samples, the splicing event led a
24-nucleotide in-frame deletion and an additional valine encoded by a
GTT codon (Figure 6)
. TrkC kinase primers
allowed the amplification of two 571- and 613-bp fragments
corresponding to the two alternatively spliced
transcripts.13
The shortest transcript was
dominant in both fetal and adult bone marrow specimens, whereas the
largest fragment was dominant within brain samples (Figures 4 and 5)
.
The TrkC truncated primer set amplified a 279-bp fragment corresponding
to a human truncated isoform.13
In addition, a
144-bp fragment was amplified in both bone marrow and brain samples.
Sequencing analysis of this TrkC TK- 144-bp
fragment showed a 135-nucleotide in-frame deletion (Figure 7)
, homologous to the truncated rat
TrkCic113,15
not previously reported in human
tissue.13
The GenBank accession number for the human TrkCI
sequence (Figure 6)
is AF058389 and for the human TrkC ic113 isoform
sequence is AF058390.
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. The sequences of NT
cDNA fragments were found to be identical with the related GenBank
human sequences. All cDNA corresponding to NGF, BDNF, NT-3, and NT-4
transcripts were found to be more abundant in fetal samples than in
adult samples (Figure 8)
. These differences were found in at least two
separate experiments. Constant low levels of NGF and BDNF transcripts
were found in adult bone marrow, whereas inconstant NT-3 and NT-4
transcripts were barely detected.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our study concentrated on the identification of cells expressing NT receptors, which may represent targets for locally synthesized NT. Certain hematopoietic cells were found to be immunoreactive for only one member of the Trk family receptors. For example, neutrophil precursors expressed both TK+ and TK- TrkC but not TrkA or TrkB. Among the NT, NGF is unique in priming human blood basophils, which express only TrkA receptors.42 However, most cells were immunoreactive for several Trk receptors and in turn may respond to several NT. For example, an intense TrkB TK+ IR was found on mature eosinophils that were also immunoreactive for TK+ TrkC. Other cells were immunoreactive for a given catalytic TK+ receptor and for another truncated TK- receptor, like erythroblasts expressing TrkA and TK- TrkB IR. Some cells, like mastocytes or ARC, were immunoreactive for all Trk receptors. In macrophages, the weak cytoplasmic staining for all Trk receptors could result from phagocytosis and should be compared with the in situ detection of the corresponding transcripts.
A direct link between the distribution of NT receptors in the bone marrow and the peripheral function of NT is difficult to establish for several reasons. First, these functions have not yet been defined for NT other than NGF. The IR for both TK+ and TK- TrkC receptors suggests that NT3 could promote megacaryocyte differentiation, but only NGF has been studied and shown to induce platelet shape changes.29 Second, a development-related switch in the pattern of NT receptor expression may occur, as observed in embryonic sensory neurons.44 Both in the erythroid and the neutrophilic lineage, the IR for TrkA or TrkC respectively decreased in mature cells, suggesting that NT support specific stages of hematopoiesis. Indeed, NGF, in synergy with stem cell factor, supports the short-term maintenance of CD34+/CD38+ erythroid progenitors.43 Similarly, a decline in TrkB expression was observed during thymocyte differentiation,38 whereas TrkA expression was detected in activated peripheral CD4+ T cells.25 Third, the pattern of NT receptor expression may also change after cellular isolation or stimulation, thus accounting for some discrepancies. Whereas NGF promotes survival and functional properties of murine neutrophils and eosinophils,45,46 NT receptor transcripts were not detected in human peripheral blood granulocytes.37 However, the myeloid (TF1 and KG1) cells and some leukemia cell lines have been shown to express trkA transcripts.35,36,43,47 In human blood monocytes, trkA expression has been shown to decrease during macrophage differentiation22 and was absent in monocytic (U937 and THP1) cell lines.35,36 However, NGF triggers phagocytosis, parasite killing, and interleukin-1ß production by macrophages through activation of the TrkA receptor,48 whose expression can be enhanced by several inflammatory molecules.22,26 Finally, the expression of TrkA and p75LNGFR in PC12 cells was recently shown to alternate in a cell phase-specific manner.49
Whatever their differentiation stage, hematopoietic cells were not found to be immunoreactive for p75LNGFR, suggesting that NT signaling may occur through Trk receptor homodimers in such cells.19 Indeed, activation of TrkA receptors in the absence of p75LNGFR has been shown to mediate NGF biological effects in several hematopoietic cell types including the erythromyeloid human cell line K562,36 human basophils,42 rat and human mast cells, and cell lines.23,24,50 The absence of p75LNGFR is a common feature of immune or hematopoietic cells.27 However, the coexpression of p75LNGFR and TrkA has been detected in certain immune cells such as human B lymphocytes28,51 and bone marrow-derived mouse mast cells.52 In addition, bone marrow stromal cells were found to be immunoreactive for all NT receptors including p75LNGFR. As for specific sets of neurons,53 p75LNGFR may modulate the interaction of a defined NT to its specific Trk receptor on bone marrow stromal cells. p75LNGFR also signals on its own54 and triggers neuronal apoptosis in the absence of NGF-induced TrkA activation.55,56
The generation of TK+ or TK- receptor isoforms, which retain NT high-affinity binding sites, may also modulate the local function of NT.5 For example, variants with insertion in the TK+ domain of TrkC have been shown to retain autophosphorylation on NT3 binding, but could no longer phosphorylate specific cellular substrates.14 NT also bind to truncated TK- receptors, identified for TrkB and TrkC,15-18 which may function as dominant negative isoforms,20 or immunoadhesins.13 Using RT-PCR, we detected transcripts encoding for all TrkAI, TrkB, and TrkC human catalytic TK+ receptors except those encoding for the TrkAII isoform. Their absence within the fetal and adult bone marrow, as opposed to their exclusive expression in the human caudate putamen, suggests a tissue-specific regulation of the splicing event in humans that has not been observed in the rat.12 Although both TrkA isoforms are comparably activated by NGF,12 TrkAI is not activated by NT3,57 which might exclude cross-talk between NT3 and TrkA at the bone marrow level. Two analogous spliced TrkC isoforms identified in the human nervous system13 were also detected in the bone marrow. The nucleotide sequence of the shortest transcript was further characterized by showing that the splicing event results in the deletion of 9 amino acids in the ECD but with an additional valine. Two transcripts differing by a nucleotide sequence encoding for a 14-amino acid insertion in the TrkC TK+ domain were detected in the bone marrow as they were in human central nervous system.13 The detection of transcripts encoding for the homologues of rat TrkBT1 TK- receptor18 and rat TrkCic158 TK- and TrkCic113 TK- receptors15 shows that the expression pattern of trk family genes is as complex in the bone marrow as it is in the nervous system.
Similar levels of transcripts encoding for TK+ and TK- receptors of the Trk family were detected from fetal stages to adulthood. The higher abundance of NT transcripts at fetal stages paralleled a higher content of stromal cells, arguing for their role in the local biosynthesis of NT. During development, NGF may be synthesized by mesenchymal target cells of sensory and sympathetic neurons.58 NGF or trkA expression may also be supported by osteoblasts or osteoclasts.59 Interestingly, the murine bone marrow stromal cell line MS-5 has been shown to produce both NGF and stem cell factor.43 The constitutive expression of several NT in certain leukemia cell lines and in human cord blood-derived mast cells also suggests an autocrine role for NT on hematopoietic cells.24,47 The cellular source of NT within the bone marrow needs to be further characterized by cellular separation or in situ hybridization studies. The wide distribution of NT receptors in the bone marrow suggests that NT may play an important role during the onset of hematopoiesis and on the differentiation of specific hematopoietic progenitors and precursors throughout life. The comparative study of hematopoietic progenitors isolated from normal mice and from knockout animals for either trk or NT genes may help to investigate these interactions. Finally, the presence of NT receptors on bone marrow stromal and hematopoietic cells highlights the potential side effects of systemic administration of NT in neurodegenerative diseases.60
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Acknowledgements |
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Footnotes |
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Supported by grants from the Région Aquitaine and the Association de Recherche contre le Cancer.
Accepted for publication November 5, 1998.
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