Department of Cellular and Molecular Medicine and Center for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5
Submitted 29 December 2003 ; accepted in final form 6 February 2004
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ABSTRACT |
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motor neurons; neuromuscular development; neurotrophins
BDNF has been shown to be an excellent candidate for the survival of both cultured motor neurons and injured motor neurons (4, 18, 19, 28, 33, 37, 46, 47, 49). BDNF supports the survival of neurons through binding to its receptors, TrkB and/or p75, which leads to the activation of an intracellular phosphorylation cascade that culminates in specific transcriptional and translational events (1). In this context, it is important to note that motor neurons innervating hindlimb muscles express both TrkB and p75 throughout postnatal development (13, 26).
Newborn BDNF-null mice do not exhibit any loss in the number of motor neurons (5, 17, 20, 21), suggesting that BDNF acts as a motor neuron survival factor during postnatal development and/or that other factors, such as NT-4/5, can functionally compensate for the lack of BDNF during embryogenesis. Interestingly, BDNF is expressed in embryonic and neonatal hindlimb muscles (13, 18) and is retrogradely transported to motor neuron cell bodies (7, 48). Expression of BDNF is restricted to a subset of muscle fibers in embryonic hindlimb that may eventually express MyHC IIB in adults (13). Furthermore, gastrocnemius muscles, which contain many MyHC IIB fibers, also express higher levels of BDNF during neonatal development compared with muscles lacking MyHC IIB fibers (32). On the basis of these findings, we therefore hypothesized that BDNF acts as a target-derived neurotrophic factor for a subpopulation of motor neurons innervating MyHC IIB muscle fibers during neonatal development of the neuromuscular system.
In the present study, we have specifically tested this hypothesis. To determine the role of muscle-derived BDNF in the survival and maturation of a subpopulation of motor neurons innervating MyHC IIB fibers, we subjected newborn rats (P5) to sciatic nerve crush and then treated them with CNTF, BDNF, or a combination of both. Such combined administration of neurotrophins (i.e., CNTF + BDNF) is known to have synergistic effects on cultured motor neurons (50). Moreover, in our recent work (31), we treated newborn rats with CNTF + NT-3 and with CNTF + NT-4/5 after P5 neonatal nerve injury, which resulted in a greater recovery of muscle mass and motor units compared with single neurotrophin treatments, which were without effects (31). We present here the results of a parallel series of experiments in which CNTF and BDNF were coadministered after P5 sciatic crush. We observed the survival of MyHC IIB fibers in EDL and TA muscles 3 mo after neonatal nerve crush with the combined administration of CNTF + BDNF. In addition, we quantified the expression of BDNF in muscles containing relatively large proportions of MyHC IIB fibers (EDL) in the first 2 wk of life, during which motor neurons are susceptible to target removal (24). We conclude that BDNF acts as a maturation factor for a subset of motor neurons innervating MyHC IIB-expressing fibers during neonatal development.
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MATERIALS AND METHODS |
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Enzyme-linked immunosorbent assay. The amount of BDNF was quantified from muscles and brain by using the Emax ImmunoAssay system (Promega, Madison, WI). Samples were homogenized in lysis buffer (1:1 vol/wt) containing 137 mM NaCl, 20 mM Tris·HCl (pH 8.0), 1% NP-40, 10% glycerol, 1 mM PMSF, 0.5 mM sodium vanadate, and one protease inhibitor cocktail tablet (Roche). Samples were then diluted with 4 vols of Dulbecco's phosphate-buffered saline, sonicated, and spun at 14,000 g for 30 min. The enzyme-linked immunosorbent assay (ELISA) procedure was performed according to the manufacturer's recommendations. Briefly, 96-well plates (MaxiSorp; NUNC) were coated overnight at 4°C with 1 µg/ml monoclonal BDNF antibody diluted in carbonate coating buffer (pH 9.7). The plates were then blocked with 1x block and sample buffer for 1 h. The plates were subsequently incubated for 2 h with samples and standards, washed, and incubated for another 2 h with a polyclonal BDNF antibody (0.5 µg/ml). The plates were washed thoroughly and incubated with an anti-IgY horseradish peroxidase-conjugated antibody (1:200) for 1 h. Each reaction was developed using TMB One solution for 15 min. The reaction was stopped with 1 N HCl, and the sample absorbance was measured at 450 nm with an ELISA plate reader. Neonatal hippocampal extracts were used as a positive control for the ELISA experiments. We obtained BDNF concentrations of 200300 pg/ml or 1.05 ± 0.10 pg/mg wet weight in neonatal hippocampal samples, which is in good agreement with previous findings (34).
Quantitative RT-PCR.
Total RNA was isolated from muscle and brain samples by using Trizol (Invitrogen Life Technologies, La Jolla, CA). The concentration of total RNA was determined using GeneQuant (Pharmacia). RNA samples were then diluted to 500 ng/µl and used in a RT reaction containing 5 mM MgCl2, 1x PCR buffer, 1 mM dNTP, 1 U/µl RNase inhibitor, 5 U/µl MuL V reverse transcriptase, and 2.5 µM random hexamer. RT reactions were placed in a thermocycler at 42°C for 1 h, followed by 5 min at 99°C to deactivate the enzyme. With the use of BDNF forward (5'-CGACGTCCCTGGCTGACACTTTT-3') and reverse (5'-AGTAAGGGCCCGAACATACGATTGG-3') primers, BDNF mRNA was amplified from the RT reactions (29). In these experiments, the skeletal -actin mRNA level, which was amplified using primers (forward, 5'-CGCGACATCAAAGAGAAGCT-3'; reverse, 5'-GGGCGATGATCTTGATCTTC-3'), was used as internal control (22). The PCR mix contained a final concentration of 2 mM MgCl2, 1x PCR buffer, 2.5 U/100 µl AmpliTaq DNA polymerase (PerkinElmer), and 0.8 pmol/µl primers. All PCR reactions were preheated to 94°C for 2 min. The PCR parameters were as follows: 94°C for 30 s, 60°C for 30 s, and 72°C for 30 s for the number of cycles indicated below.
In separate experiments, we ascertained that our PCR assays were within the linear range of amplification (see Fig. 6). To this end, we first reverse-transcribed total RNA and then performed several PCRs with 2-cycle increments spanning from 2640 and 820 cycles for BDNF and -actin, respectively. Subsequently, each designated PCR cycle sample was quantified on Vistra Green gels using a PhosphorImager and ImageQuant 5.1 (Molecular Dynamics, Sunnyvale, CA). By plotting cycle number vs. band intensity, we determined that 30 and 12 cycles were sufficient to obtain a reproducible signal within the linear range of PCR amplification for BDNF and
-actin, respectively (see Fig. 6). In these assays, the negative and positive samples, which consisted of RNA-free water and total brain RNA, respectively, were used in parallel in each RT-PCR experiment.
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RESULTS |
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DISCUSSION |
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BDNF in developing MyHC IIB fibers. There is a distinct temporal and spatial pattern of BDNF expression in skeletal muscle during embryonic and early postnatal development (11, 13, 14, 32). Griesbeck et al. (13) have demonstrated the expression of BDNF in developing muscle fibers adjacent to epidermal tissue of embryonic day 15 hindlimb. These developing muscle fibers are localized to the superficial areas of EDL and TA muscles, where MyHC IIB fibers are predominantly expressed in adult muscles. In the present study, we also detected, within the first 2 wk of life, a higher level of BDNF in EDL vs. soleus muscles. In accordance with our observations, Nagano and Suzuki (32) have also shown higher BDNF concentrations in the gastrocnemius muscle, which contains a high proportion of MyHC IIB fibers, compared with soleus muscles in neonatal animals. Collectively, these results demonstrate that there is preferential expression of BDNF in those developing muscle fibers that give rise to MyHC IIB fibers in adults.
The functional implication of the preferential expression of BDNF in MyHC IIB fibers during early postnatal development signifies its involvement in the electrophysiological modification of the motor neurons innervating developing MyHC IIB fibers. To date, studies that have examined the role of BDNF in modulating the electrophysiological properties of motor neurons have yielded contradictory findings (12, 35). When BDNF is applied to neuromuscular contacts in adults, motor neurons innervating gastrocnemius muscle fibers mimic the electrical properties of those innervating soleus fibers by becoming more electrically excitable (12). On the other hand, during neonatal development, BDNF decreases the excitability of motor neurons as monitored by changes in the monosynaptic sensory-to-motor inputs (35). The synaptic inputs as well as motor neurons are in a dynamic state of modification and growth during the first week after birth (36). Excitability modifications of motor neurons, which may be modulated in part by BDNF, are determined by the composition of synaptic inputs and ionic channels on motor neurons during neonatal development (35, 36). In fact, BDNF upregulates the potassium conductance that is required for high-frequency firing of motor neurons innervating MyHC IIB fibers (27). Therefore, it is conceivable that during early postnatal development, muscle-derived BDNF alters the electrical properties of motor neurons innervating MyHC IIB fibers toward those with lower excitability and a high-frequency phasic pattern of activation.
Expression of BDNF in muscles. There were similar levels of BDNF transcript in both EDL and soleus muscles from neonatal animals, whereas the amount of BDNF protein was clearly higher in EDL muscles. Because of this discordance between mRNA and protein levels, we speculate that BDNF synthesis is regulated by key translational events and/or that its secretion varies between subsets of EDL and soleus muscle fibers, hence leading to an accumulation in EDL muscles of neonates. Accumulation of BDNF in EDL muscles from neonates appears unlikely because neonatal motor neurons innervating EDL muscles require BDNF for their survival. In this context, it is important to note that the increase in BDNF protein levels seen in the hippocampus of newborns is not mirrored by an increase in the abundance of its transcripts (16). Together, these results highlight the important contribution of translational mechanisms in regulating the expression of BDNF in skeletal muscles as well as in neurons.
In adult muscles, BDNF transcripts as well as protein levels were 3040% higher in soleus than in EDL muscles, suggesting the involvement of pretranslational mechanisms in the regulation of BDNF expression. In this case, the higher levels of BDNF correlate with the activity of these muscles, because the total amount of neuromuscular activity is higher in adult soleus vs. EDL muscles (15). In fact, the activity-dependent expression of BDNF has been well characterized in neurons both in vitro and in vivo (3). In neurons, higher activity triggers higher intracellular calcium levels, which in turn activate calcium-dependent transcriptional events (39, 4345). Given that the resting intracellular calcium levels and calcium entry are significantly higher in the more active skeletal muscles such as the soleus (9), these results strongly suggest that expression of BDNF in adult muscle is under the control of activity-regulated mechanisms that involve calcium signaling.
Effects of BDNF vs. NT-3 or NT-4/5. Studies performed with adult animals suggest a preferential role for other neurotrophins in the rescue of MyHC IIB fibers and their motor neurons. For example, Sterne et al. (40) have shown the rescue of MyHC IIB fibers in gastrocnemius muscles after treatment with NT-3 after axotomy in adults (40). However, we did not observe any MyHC IIB fibers in EDL muscles from CNTF + NT-3-treated animals 3 mo after neonatal sciatic crush, even though CNTF + NT-3 was able to have beneficial effects on the number of motor units and total number of EDL muscle fibers (31). The expression of NT-3 has been localized to most muscle fibers during embryogenesis, especially in those located in the deeper regions of the hindlimb such as in the soleus (13). Therefore, we speculate that NT-3, which may have beneficial effects for MyHC IIB fibers in adults, does not act as a maturation factor for motor neurons innervating MyHC IIB fibers during early development of the neuromuscular system.
Because BDNF and NT-4/5 bind with similar affinities to TrkB and/or p75, we expected to observe a similar rescue of MyHC IIB motor units in EDL muscles from animals subjected to neonatal nerve crush and treated with CNTF + BDNF or CNTF + NT-4/5. However, the EDL muscles from animals treated with CNTF + NT-4/5 after neonatal sciatic nerve crush did not contain any MyHC IIB fibers (31). Nonetheless, the administration of CNTF + NT-4/5 was more effective in rescuing motor units of EDL after neonatal nerve injury (31). During embryogenesis, the expression of NT-4/5 has been localized to the epidermal tissue, whereas BDNF transcripts are found in developing muscle fibers of the hindlimb (13). The expression of BDNF and NT-4/5 is activity dependent and has been localized to slow muscle fibers in adult soleus muscles (10). Also, NT-4/5 and BDNF have been shown to shift the MyHC expression profile of muscle fibers and electrophysiological properties of motor neurons, respectively, toward a slower phenotype (2, 12). These data suggest that although BDNF and NT-4/5 have redundant roles in adults, they may have different functions during embryogenesis and early postnatal development. In fact, replacing the BDNF locus with NT-4/5 results in the rescue of many BDNF-null sensory deficiencies but suggests different functions through different variants of TrkB (8). Naturally occurring splice variants of TrkB have different affinities for BDNF and NT-4/5 (42). Thus it is plausible to consider the existence of different intracellular signals initiated from the splice variants of TrkB, leading to different cellular functions depending on the presence of BDNF or NT-4/5 during motor or sensory neuronal development (30).
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GRANTS |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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