Montreal Neurological Institute and Biology Department, McGill University, Montreal, Quebec, Canada H3A 2B4
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ABSTRACT |
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Little is known of the gene regulatory mechanisms that coordinate the contractile and metabolic specializations of skeletal muscle fibers. Here we report a novel connection between fast isoform contractile protein transgene and glycolytic enzyme expression. In quantitative histochemical studies of transgenic mouse muscle fibers, we found extensive coregulation of the glycolytic enzyme glycerol-3-phosphate dehydrogenase (GPDH) and transgene constructs based on the fast skeletal muscle troponin I (TnIfast) gene. In addition to a common IIB > IIX > IIA fiber type pattern, TnIfast transgenes and GPDH showed correlated fiber-to-fiber variation within each fast fiber type, concerted emergence of high-level expression during early postnatal muscle maturation, and parallel responses to muscle under- or overloading. Regulatory information for GPDH-coregulated expression is carried by the TnIfast first-intron enhancer (IRE). These results identify an unexpected contractile/metabolic gene regulatory link that is amenable to further molecular characterization. They also raise the possibility that the equal expression in all fast fiber types observed for the endogenous TnIfast gene may be driven by different metabolically coordinated mechanisms in glycolytic (IIB) vs. oxidative (IIA) fast fibers.
muscle gene regulation; metabolic gene expression; muscle fiber phenotype
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INTRODUCTION |
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EACH DIFFERENTIATED CELL PHENOTYPE involves multiple, functionally coordinated, cellular specializations. Skeletal muscle provides striking examples of coordinated specializations in terms of contractile function and energy metabolism. Skeletal muscle fibers contain high levels both of contractile proteins and of ATP-producing metabolic enzymes, which together make possible the extremely high energy flux of actively exercising muscle (22, 36). Moreover, muscle fibers are biochemically and physiologically specialized, with different fibers expressing functionally distinct contractile protein isoforms (45, 54) and different relative amounts of oxidative vs. glycolytic metabolic enzymes (21, 43, 44, 51). These specialized features are related to, and are at least partly determined by, motor unit usage patterns and are thought to represent coordinated optimizations of muscle fiber contractile and metabolic properties for differing usage profiles (6, 47, 54). Reporter transgene studies indicate that muscle fiber contractile and metabolic specializations are based largely on gene transcriptional regulation (1, 13, 19, 27, 30, 50, 52), but almost nothing is known of the specific mechanisms that coordinate contractile and metabolic gene expression.
The majority of mammalian muscle fibers fall into one of several distinct contractile/metabolic phenotypes termed fiber types. Slow (type I) fibers express "slow" isoforms of myosin heavy chain and many other contractile proteins (45, 54), high or intermediate levels of oxidative enzymes, and lower levels of glycolytic enzymes than are found in fast fibers (21, 43, 44, 51). Several distinct fast fiber types [IIA, IIB, IIX (also called IID)] exist, which express different fast myosin heavy chain isoforms (45, 54) and have glycolytic enzyme levels that vary from high (in IIB fibers) to low (in IIA fibers) and inversely varying oxidative enzyme levels (21, 43, 51). Thus muscle fibers can be ordered in a metabolic spectrum, a continuum of increasing glycolytic enzyme levels, on which the fiber types fall in a characteristic order: I-IIA-IIX-IIB (51). This order also appears to correspond to a motor unit usage spectrum, with frequency of use decreasing from left to right (20).
Muscle fiber phenotype is plastic. Perturbations of neuromuscular activity patterns or muscle mechanical loading can result in fiber type transformations that involve both contractile protein isoform switches and changes in metabolic enzyme levels (4, 35, 46, 47). In general, such transformations occur in steps between adjacent positions on the I-IIA-IIX-IIB fiber type spectrum. Rightward transformations caused, e.g., by reducing neuromuscular activity or mechanical load, elevate glycolytic enzyme levels (34, 35, 60). Conversely, leftward transformations, e.g., those caused by increasing activity or load, reduce glycolytic enzyme levels (4, 14, 49, 61).
The existence of a characteristic order of the fiber types on the glycolytic spectrum, and the occurrence of coordinated contractile and metabolic changes in fiber type transformation experiments, imply the existence of regulatory mechanisms that integrate metabolic and contractile protein gene expression.
Current knowledge of adult muscle gene regulation mostly concerns mechanisms that operate at the left end of the I-IIA-IIX-IIB fiber type spectrum, in highly active motor units expressing slow contractile protein isoforms and/or high levels of oxidative, and low levels of glycolytic, enzymes (7, 9, 12, 15, 23, 38, 42, 66, 67). Among several activity-regulated factors, at least one, the Ca2+-dependent protein phosphatase calcineurin, plays a role in the expression both of slow isoform contractile protein genes (9, 12, 66) and of a gene related to oxidative metabolism, myoglobin (9), and hence represents a candidate contractile/metabolic coordination mechanism.
Much less is known of regulatory mechanisms at work at the right end of the I-IIA-IIX-IIB fiber type spectrum, which is characterized by less frequent contractile activity, high-level glycolytic gene expression, and fast isoform contractile protein gene expression (6, 20). Several fast isoform contractile protein genes (13, 19, 28, 65) and glycolytic enzyme genes (5, 33, 52, 56) have been studied, but signaling pathways controlling fiber type-related differential expression have yet to be delineated. In the genes encoding creatine kinase and the glycolytic enzyme aldolase A, DNA cis-elements have been identified that differentially affect expression in subsets of IIB fiber-enriched muscles (55, 56, 58). However, the relationship of these elements to fiber type-specific gene expression or contractile activity levels is unknown. An E-box has been implicated in the fiber type-specific expression of the IIB myosin heavy chain gene (65), but it is also known that E-boxes are not involved in high-level expression of the creatine kinase or aldolase A promoters in fast glycolytic (i.e., IIB) fibers (55, 58). Thus research to date has not identified a specific molecular framework for investigating the mechanisms that coordinate fast contractile protein and glycolytic enzyme gene regulation. In the present report we describe a novel and experimentally accessible coordination between fast isoform contractile protein transgene and glycolytic enzyme expression. These findings emerged from our studies of the gene encoding the fast skeletal muscle isoform of the contractile regulatory protein troponin I (TnIfast).
We have previously reported an unexplained behavior of TnIfast gene constructs in transgenic mice, i.e., differential expression among the fast fiber types in a IIB > IIX > IIA pattern (19). This pattern was a departure from the behavior of the endogenous TnIfast gene, which is expressed at equal levels in all fast fiber types. A similar, unexplained, IIB > IIX > IIA pattern has been observed for a variety of other contractile protein transgene constructs (13, 16, 27). In an attempt to relate the IIB > IIX > IIA pattern to biologically significant differences among the fast fiber types, we have analyzed the relationship between TnIfast transgene expression and metabolic enzyme levels, using glycerol-3-phosphate dehydrogenase (GPDH) and succinate dehydrogenase (SDH) as indicators of glycolytic and oxidative expression. Our results reveal a strong link between TnIfast transgene and GPDH expression and show that the common IIB > IIX > IIA expression profile of these genes is part of a remarkably broad pattern of coregulation. Other aspects of coregulation include covariation in expression levels among individual fibers within each of the fast fiber types, parallel emergence of differential expression during early postnatal muscle maturation, and parallel responses to experimental muscle under- or overloading. Our results also show that the IRE, a well-characterized muscle-specific enhancer in the TnIfast gene's first intron, carries the regulatory information for GPDH-coregulated expression.
The extensive similarities between IRE-driven TnIfast transgene expression and GPDH expression imply a novel and intimate gene regulatory relationship. By documenting quantitative coregulation, and by localizing the relevant regulatory information to a small DNA fragment, these findings greatly consolidate the notion of a coordinating mechanism between fast isoform contractile protein genes and glycolytic enzyme genes and open a way to its further characterization. In addition, our findings provide new insight into the previously unexplained IIB > IIX > IIA expression pattern shown by TnIfast and other muscle transgenes, which is now seen to reflect coordinated expression with glycolytic enzyme genes. That this aspect is not evident in the behavior of the endogenous TnIfast gene suggests an unexpected heterogeneity of mechanisms driving high-level gene expression of the TnIfast gene, and likely other genes as well, in the different metabolically specialized fast fiber types.
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MATERIALS AND METHODS |
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DNA constructs and transgenic mice.
Production of TnILacZ1 transgenic mice has been described previously
(19). The TnILacZ1 construct contains 530 bp of upstream DNA, the first exon, first intron, and the first (untranslated) part of
the second exon of the quail TnIfast gene, linked to the Escherichia coli LacZ -galactosidase (
-gal) gene and
SV40 splicing and polyadenylation sequences. Two independent transgenic
lines, 29 and 36, were used. Unless indicated otherwise, data presented are from line 29. We also have produced 3xIRE-tkLacZ transgenic mice
(unpublished work). 3xIRE-tkLacZ contains three copies of a
148-bp IRE-containing DNA fragment (68), two upstream and one downstream, of a heterologous reporter gene consisting of the
105
to +57 herpes virus thymidine kinase (tk) promoter (37) linked to the same LacZ/SV40 DNA elements used in TnILacZ1. Two independent lines, 19 and 69, were used. In all cases hemizygous male
or female animals >6 wk old were used, unless otherwise indicated.
Histochemistry.
Histochemistry was done on serial cross-sections of frozen muscles that
were collected on glass coverslips. Sections were of 10-µm or 8-µm
thickness for adult or perinatal/juvenile muscle, respectively. -Gal
histochemistry using X-Gal was as previously described
(19), with room temperature incubation for 20 h. GPDH and SDH histochemical reactions were at 37°C for 30 min or, in some
cases, 10 min (see below). GPDH reaction conditions (0.1 M
sodium phosphate buffer, pH 7.4, 1 mM sodium azide, 0.8 mM phenazine methosulfate, 1.2 mM nitro blue tetrazolium, and 9.3 mM
-glycerol phosphate) were based on Dunn and Michel (14). Both
cytoplasmic (EC 1.1.1.8) and mitochondrial (EC 1.1.99.5) GPDH enzymes of the glycerol phosphate shuttle may contribute to the activity detected (51). SDH reaction conditions (0.1 M
Tris · HCl, pH 7.5, 1 mM sodium azide, 1 mM phenazine
methosulfate, 1.5 mM nitro blue tetrazolium, 5 mM EDTA, and 48 mM
disodium succinate) were based on the work of Blanco et al.
(3) and Nolte and Pette (41). After
histochemical reactions, tissue sections were rinsed extensively with
water and mounted for microscopy with polyvinyl alcohol resin
(Immu-Mount, Shandon).
Under- and overload experiments.
Hindlimb muscles, including the soleus, were underloaded by hindlimb
suspension carried out as described by McCarthy et al. (34) for 14 days. Plantaris muscle overload experiments,
also of 14 days in duration, were based on bilateral ablation of
synergist muscles, the soleus and gastrocnemius (61, 62)
as follows. In chloral hydrate-anesthetized mice, the biceps femoris
muscle was sectioned along its lateral aspect, following the junction of the peroneus longus muscle and the lateral head of the gastrocnemius muscle. These latter were separated to reveal the soleus muscle, which
was removed from tendon to tendon. At the ankle, tendons attaching the
lateral and medial heads of the gastrocnemius muscle were isolated from
the plantaris tendon, the tibial and plantar nerves, and the
saphenous blood vessels. Both gastrocnemius tendons were sectioned, and
the entire muscle was removed at the knee. Within each under- or
overload experiment, all animals, control and treated, were same-age
siblings, and all sections were coprocessed for GPDH or -gal
histochemistry so as to be directly comparable. Care and use of animals
followed guidelines of the Canadian Council for Animal Care under
protocols approved by the McGill University Animal Care Committee.
Statistical analysis was performed at the VassarStats website
(http://faculty.vassar.edu/~lowry/VassarStats.html#menu) created and maintained by Richard Lowry, Department of Psychology, Vassar College, Poughkeepsie, NY.
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RESULTS |
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TnILacZ1 -gal expression levels correlate with glycolytic enzyme
levels in adult muscle.
TnILacZ1 is a TnIfast/
-gal reporter construct that shows a IIB > IIX > IIA > I fiber type differential expression pattern in
transgenic mouse skeletal muscle (19). We investigated the relationship between TnILacZ1 transgene expression and metabolic gene
expression by histochemical analysis of serial cryostat sections of
hindlimb muscles for TnILacZ1-encoded
-gal and for marker enzymes of
glycolytic or oxidative metabolism. We chose GPDH as the marker
glycolytic enzyme because a histochemical stain has been developed and
because GPDH levels correlate well with other glycolytic enzymes in
skeletal muscle (45). We used SDH as a marker for
oxidative enzyme expression levels (14, 51).
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Developmental coemergence of TnILacZ1 -gal and GPDH
high-level expression.
The similarity of TnILacZ1 and GPDH expression patterns in adult
muscle fibers raised the question whether these patterns arose through
similar developmental mechanisms. We have previously shown that TnIfast
transgene IIB > IIX > IIA differential expression among the fast
fiber types emerges during the first weeks of postnatal life, when the
IIB, IIX, and IIA adult fast fiber types themselves arise through
differential activation of the IIB, IIX, and IIA myosin heavy chain
genes (19). [Before activation of the adult genes,
immature fast fibers express the perinatal/neonatal fast myosin heavy
chain isoform MHCperi/neo (11).]
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TnILacZ1 expression is not consistently correlated with SDH levels. Glycolytic and oxidative enzyme levels in skeletal muscle fibers tend to be inversely related, but this is not a strict, or general, rule. For example, GPDH was at higher levels in IIA fibers than in type I fibers in any muscle, and SDH showed a parallel, not an inverse, relationship (Fig. 3; see also Refs. 14 and 51). Likewise, both enzymes were at higher levels in adult muscle than in neonatal muscle (Fig. 5 and data not shown). In addition, while GPDH was at higher levels in plantaris IIA fibers than in soleus IIA fibers, SDH levels were similar in the two muscles (Fig. 4). In each of these comparisons, we found that TnILacZ1 expression levels were higher in the comparison partner having higher GPDH levels (Figs. 3-5). Thus TnILacZ1 expression showed a consistent positive correlation with glycolytic enzyme levels but did not show a consistent inverse correlation with oxidative enzyme levels. Therefore, in terms of metabolic specialization, TnILacZ1 transgene expression appears to be linked to the glycolytic system per se, and not (inversely) to the oxidative system or to the overall metabolic profile, i.e., glycolytic/oxidative ratio.
Correlated responses of GPDH and TnILacZ1 -gal expression to
under- and overloading.
Glycolytic enzyme levels in muscle respond to use/disuse and changes in
mechanical loading. The markedly similar expression profiles of the
TnILacZ1 transgene and GPDH both in adult and developing muscle led us
to question whether the TnILacZ1 transgene might also respond to under-
and overloading. Hindlimb suspension is an underloading model that has
previously been shown to elevate glycolytic enzyme (34)
and TnIfast protein (8) levels in the soleus muscle. We
found that hindlimb suspension of TnILacZ1 transgenic for 14 days also
led to increases in
-gal staining that were evident on inspection
(Fig. 6) and confirmed by
microdensitometry (Fig. 7A).
Moreover, there was a significant correlation between GPDH and
-gal
levels in individual fibers in the hindlimb-suspended soleus as shown
in the scatterplot in Fig. 8B,
indicating that the fibers that upregulated TnILacZ1 expression to the
greatest extent were also the fibers that upregulated GPDH to the
greatest extent. We also found that TnILacZ1
-gal expression was
downregulated in all fiber types in plantaris muscle following 14 days
of overload by synergist ablation (Fig. 7B), which has been
shown to downregulate glycolytic enzyme expression, including GPDH
(14). Scatterplot analysis (Fig. 8, C and
D) confirmed that overloading did not perturb the overall
-gal/GPDH correlation in plantaris muscle, indicating that, at the
individual fiber level, decreased
-gal expression was associated
with decreased GPDH expression, and vice versa. Thus TnILacZ1 transgene
expression responds to under- and overloading in parallel with
glycolytic enzyme genes.
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TnIfast IRE enhancer drives GPDH-correlated expression.
The TnIfast gene contains an enhancer in the first intron, the IRE
(31, 68), that drives much of the gene's regulatory behavior. The IRE, when linked to heterologous promoters, drives gene
expression that is activated during myoblast differentiation in
transfected muscle cell culture lines and is fast muscle specific in
transgenic mice (31, 40, 68, and unpublished observations). We have
prepared transgenic mice carrying a heterologous -gal reporter
construct, 3xIRE-tkLacZ, in which the herpes virus thymidine kinase
promoter is driven by three copies of the 148-bp IRE. Like TnILacZ1,
3xIRE-tkLacZ is expressed specifically in skeletal muscle, and in a IIB > IIX > IIA pattern that emerges during early postnatal life
(unpublished observations). Examination of within-fiber-type variation
by quantitative microdensitometry showed that
-gal expression
correlated with GPDH levels. As shown in Table 1, a positive
correlation coefficient r was obtained in 10/12
within-fiber-type comparisons involving two independent 3xIRE-tkLacZ
transgenic lines, and in all of these cases the correlation achieved
statistical significance at the P < 0.01 level. This
result shows that the IRE drives heterologous gene expression in a
pattern that correlates with GPDH expression.
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DISCUSSION |
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Our results reveal a novel and very close relationship between glycolytic enzyme and contractile protein transgene regulation in skeletal muscle fibers. Previous studies had identified qualitative relationships between expression of particular myosin isoforms and metabolic enzyme levels (14, 43, 51). Here we show for the first time a quantitative correlation between expression levels of a contractile protein transgene and a metabolic enzyme. Our findings provide both the initial evidence for a novel contractile/metabolic coordinating mechanism and a molecular genetic context for its further study. They also generate new insight into an unexplained IIB>IIX>IIA expression pattern observed for several contractile protein transgene constructs (13, 16, 19, 27), and this has implications for our understanding of the mechanisms that drive high-level gene expression in adult fast muscle fibers.
Similarity of TnIfast transgene and glycolytic enzyme expression profiles. Our results show that the TnIfast transgene construct TnILacZ1 is differentially expressed among muscle fibers at levels that correlate with levels of the glycolytic indicator enzyme GPDH. An inverse correlation with oxidative enzyme (SDH) levels was less complete than the positive correlation with GPDH, indicating that TnILacZ1 expression is linked specifically to glycolytic enzyme levels and not, inversely, to oxidative enzymes or to muscle fiber overall metabolic profiles. In addition to their markedly similar expression patterns in adult muscle fibers, including a IIB > IIX > IIA > I fiber type pattern, TnILacZ1 and GPDH show important regulatory parallels during postnatal development; high-level expression emerges at the same time and in the same fibers during muscle maturation. Moreover, we found that the TnILacZ1 transgene responds to muscle under- and overloading in a manner parallel to that previously established for glycolytic enzymes (14, 34, 61). This extensive coregulation suggests that common, or thoroughly integrated, mechanisms drive expression of TnILacZ1 and GPDH genes. Because GPDH expression is a good indicator of glycolytic gene expression in general (45), TnILacZ1 expression is presumably integrated not uniquely with GPDH but with a metabolic regulatory system controlling many glycolytic enzyme genes. Regulatory information for GPDH-coregulated expression is carried by the TnIfast first-intron enhancer, the IRE.
In our studies we observed only one apparent difference between TnILacZ1 and GPDH expression patterns. TnILacZ1 showed preferential expression in fast fibers in perinatal (PND 3) muscle. This is consistent with the known two-stage developmental emergence of the TnILacZ1 fiber type pattern, namely, 1) a prenatally established preferential expression in fast, as opposed to slow, fibers, and 2) a postnatally induced differential superactivation within the maturing fast fiber population to generate IIB > IIX > IIA expression (19). In contrast, GPDH did not show differential expression in fast and slow fibers at PND 3, suggesting that it does not share the first regulatory mechanism (although it apparently does share the second mechanism, leading to IIB > IIX > IIA expression postnatally). However, other glycolytic enzymes,Nature of the coordinating mechanism. In experimental fiber type transformation experiments, changes in metabolic enzyme levels generally precede contractile protein isoform switches (reviewed in Ref. 48), and it has been suggested that glycolytic enzyme changes may have a regulatory role in signaling, through unknown mechanisms, to contractile protein genes (14). Such serial regulation could account for coexpression of TnILacZ1 and glycolytic enzyme genes. However, there is no direct evidence for such regulatory pathways, and it remains possible that TnILacZ1 and glycolytic enzyme genes are independently reacting to common, or integrated, upstream signals.
Cellular fiber type identity is a signal that could potentially coordinate fiber-to-fiber differences in the expression of various genes. However, we do not find that TnILacZ1 or GPDH are expressed at distinct, characteristic levels in each fiber type. Rather, expression levels form smoothly varying continuums within, as well as among, the fast fiber types. The within-fiber-type correlation between TnILacZ1 and GPDH levels indicates that the fiber-to-fiber differences observed in both enzymes represents real variation and cannot be due solely to random measurement errors. Moreover, gradation of TnILacZ1 or GPDH levels within a fiber type does not solely reflect the blending of distinct fiber type-specific levels in hybrid or intermediate fibers, because hybrid fibers usually constitute only a small minority and because variation is clearly evident in our data within the IIX fiber type, which by our typing method does not include hybrid fibers (see MATERIALS AND METHODS). These results indicate that TnILacZ1 and GPDH differential expression among fast fibers is not determined by cellular fiber type identity. Rather, expression levels reflect an intracellular gene regulatory parameter that varies smoothly, rather than in a quantal or saltatory manner, as fiber type does. The molecular nature of the hypothetical smoothly graded signal is unknown, but its activity is likely to be inversely related to muscle fiber contractile activity. Intracellular Ca2+ exposure is a correlate of contractile activity that has been implicated, through calcineurin (9, 12, 66) and protein kinase C (18) pathways, in the high-level expression of oxidative metabolic enzymes and slow isoform contractile protein genes in highly active motor units. It is possible that Ca2+-sensing molecules could also play a role in the relationship between contractile activity and TnILacZ1/glycolytic enzyme gene expression, although in this case the net effect of elevated Ca2+ levels would be to repress rather than augment gene expression. The within-fiber-type correlation between GPDH and 3xIRE-tkLacZThe IRE enhancer and mechanisms of high-level gene expression in adult fast fibers. The IRE is the principal known regulatory element of the TnIfast gene. It drives gene activation during myoblast differentiation in culture (31) and skeletal muscle-specific expression in vivo (40 and unpublished observations). These activities can readily be related to the endogenous TnIfast gene, which is also activated during myoblast differentiation and is skeletal muscle specific (29). On the other hand, the IRE-driven IIB > IIX > IIA pattern does not correspond to the pattern of endogenous TnIfast gene expression, which is equal expression in all fast fiber types (19, 29). A number of other contractile protein transgenes also unexpectedly show IIB > IIX > IIA differential expression among the fast fiber types (13, 16, 27), suggesting that a broadly relevant common mechanism is at work. Our results provide a biological context for understanding the IIB > IIX > IIA pattern by showing that it represents part of a larger pattern of coordinated expression of contractile protein transgenes with glycolytic enzyme genes. Our results further suggest that different mechanisms may drive high-level expression of the endogenous TnIfast gene in the most-glycolytic (IIB) vs. the most-oxidative (IIA) fast fibers.
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ACKNOWLEDGEMENTS |
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We thank Richard Tsika for sharing expertise regarding the hindlimb-suspension protocol and Stefano Schiaffino for providing antibodies. The A4.840 and N3.36 antibodies, developed by Helen Blau, were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of National Institute of Child Health and Human Development and maintained by The University of Iowa, Department of Biological Sciences, Iowa City, IA.
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FOOTNOTES |
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This research was supported by the Medical Research Council of Canada/Canadian Institutes of Health Research.
K. E. M. Hastings is a Killam Scholar of the Montreal Neurological Institute.
Address for reprint requests and other correspondence: K. Hastings, Montreal Neurological Institute and Biology Dept., McGill Univ., 3801 University St., Montreal, Quebec, Canada H3A 2B4 (E-mail: khastings{at}mni.mcgill.ca).
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.
First published September 21, 2001; 10.1152/ajpcell.00294.2001
Received 28 June 2001; accepted in final form 11 September 2001.
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