1 Neuroscience Program and 2 Department of Molecular and Integrative Physiology, University of Illinois, Urbana, Illinois 61801
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ABSTRACT |
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Although the adrenal cortex and medulla are both involved in the maintenance of homeostasis and stress response, the functional importance of intra-adrenal interactions remains unclear. When primary cocultures of frog (Rana pipiens) adrenocortical and chromaffin cells were used, selective chromaffin cell activation dramatically affected both chromaffin and adrenocortical cells. Depolarization with 50 µm veratridine enhanced chromaffin cell neuronal phenotype, contacts with adrenocortical cells, and secretion of norepinephrine, epinephrine, and serotonin. Time-lapse video microscopy recorded the rapid establishment of growth cones on the activated chromaffin cell neurites, neurite branching, and outgrowth toward adrenocortical cells. Simultaneously, adrenocortical cells migrated toward chromaffin cells. Following chromaffin cell activation, adrenocortical cell Fos protein expression and corticosteroid secretion were increased, indicating that chromaffin cell modulation of adrenocortical cells is at the transcriptional level. These results provide evidence that intra-adrenal interactions affect cellular differentiation and modulate steroidogenesis. Furthermore, this suggests that the activity-related plasticity of chromaffin and adrenocortical cells is developmentally and physiologically important.
time-lapse video microscopy; sympatho-endocrine interaction; adrenocortical; adrenal medulla; steroidogenesis; neural plasticity
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INTRODUCTION |
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ALTHOUGH THE ADRENAL CORTEX and the adrenal medulla are often considered separate functional units, the coexistence of the two embryologically distinct tissues within one organ and the demonstration of their physiological interactions suggest that communication between medullary and adrenocortical cells contributes to their optimal function (6, 18, 24, 39). Examples of functional interactions include the maintenance of chromaffin cell phenotype by corticosteroids (13, 39) and the modulation of steroidogenesis by the neurotransmitters and neuropeptides expressed by chromaffin cells (10, 11, 16, 38). The mammalian adrenal is organized such that a central medulla is surrounded by a zonated adrenal cortex with centripetally directed blood flow (37), providing the mechanism by which adrenocortical cell products directly affect medullary cells. On the basis of this organization, however, it is unlikely that medullary products affect adrenocortical cells via vascular perfusion. Alternatively, neuronal and paracrine interactions are the likely mechanisms for medullary control of adrenocortical function in mammals (4, 15, 19). Medullary ganglion cells, including a prominent vasoactive intestinal peptide (VIP)-expressing population (18), extend neurites radially through the inner zones of the cortex to form a plexus in the outermost zone, the zona glomerulosa, thus providing a morphological substrate for medullary (neuronal) control of adrenocortical function (19). On the other hand, paracrine interactions likely occur between the chromaffin and adrenocortical cells located in the innermost zone of the cortex, the zona reticularis, and/or between extramedullary chromaffin cells and adrenocortical cells (4). It is noteworthy that in the adrenals of those vertebrates in which chromaffin cells and adrenocortical cells are intermixed (e.g., some fishes, amphibians, birds, and reptiles), the paracrine mechanism is likely to account for much of the cellular interaction (24).
To study the cellular interactions between chromaffin and adrenocortical cells, we developed primary cocultures of frog adrenal cells (31). The frog adrenal is used as a model because its innate characteristics are likely to facilitate interactions between chromaffin and adrenocortical cells; these characteristics include the intermixing of the two cell types and the extension of short processes by chromaffin cells. In addition, we observed intrinsic neurons within the frog adrenal that may mimic the intrinsic innervation of the mammalian adrenal (unpublished observations and Ref. 18). Chromaffin and adrenocortical cells maintain many characteristics in coculture, including the expression and release of neurotransmitters, neuropeptides, aldosterone, and corticosterone; thus these cocultures are a useful model to study their cellular interactions (31).
In response to homeostatic challenge, many tissues undergo phenotypic changes such as the increased growth and secretion of the zona glomerulosa following dietary sodium restriction or the atrophy of the zona fasciculata and zona reticularis following hypophysectomy (7). Although comparable responses in chromaffin cell phenotype are not as well characterized, these cells clearly exhibit plasticity of neurotransmitter and neuropeptide expression during development and aging (9, 14). Acute depolarization of cultured bovine chromaffin cells induces rapid filopodial formation (26), whereas chronic depolarization induces neurite formation (35), suggesting that depolarization may stimulate the modification of morphology and functional connections. Environmental factors such as nerve growth factors (NGF) and glucocorticoids are also reported to affect chromaffin cell phenotype (1, 13).
In the process of our investigation of the effect of chromaffin cell activation on steroid secretion, we noted a resultant dramatic change in chromaffin cell morphology into a more neuronal-like configuration. In the present study, we characterize cellular interactions between chromaffin and adrenocortical cells following chromaffin cell activation using carbamylcholine (CCh), a cholinergic agonist that affects both nicotinic and muscarinic cholinergic receptors, and veratridine. Veratridine acts on voltage-sensitive sodium channels to increase sodium influx and thus depolarizes chromaffin cells and induces catecholamine release (21). Adrenocortical cells lack voltage-dependent sodium channels (27) and are, therefore, unaffected directly by veratridine, as was verified in our previous studies (30). In the present study, we show that short-term chromaffin cell activation increased Fos protein expression and corticosterone secretion, indicating that chromaffin cell modulation of adrenocortical cells occurs at the transcriptional level. The more neuronal-like morphology of chromaffin cells and increased apparent contacts between chromaffin and adrenocortical cells observed following prolonged chromaffin cell activation suggest that activity-related plasticity enhances their interactions.
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MATERIALS AND METHODS |
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Cell culture.
Frog (Rana pipiens) adrenal cocultures were prepared as
described previously (31). Briefly, the adrenal tissue was
dissected from the ventral surface of the kidney, minced, and
dissociated with enzymes (2 mg/ml collagenase A, 1.6 mg/ml dispase, and
0.1 mg/ml DNase I; all from Boehringer Mannheim, Indianapolis, IN), triturated, and then cultured at a density of 1.3 × 104 cell/cm2 on glass coverslips (Bellco Glass,
Vineland, NJ) or 35-mm culture dishes (Falcon Plastics) on laminin
(Sigma, St. Louis, MO) plus poly-D-lysine substrates
(Sigma) in supplemented 55% Leibowitz-15 medium (L-15; Sigma)
(31). The medium also contained 5% fetal bovine serum
(Atlantic Biologicals, Norcross, GA), mouse NGF 2.5 s (50 ng/ml;
Alomone Labs, Jerusalem, Israel), and basic fibroblast growth factor
(human recombinant, 10 ng/ml; Bachem, Torrance, CA).
Supplemented medium with histamine (2 µg/ml, Sigma) to optimize neurite outgrowth, adrenocorticotropic hormone (ACTH) 1-24
(1010 M, Sigma), 5% fetal calf serum to maintain basal
steroidogenesis, and sometimes cytosine
-D-arabinofuranoside (10
6 M) to inhibit
cell proliferation (31) were used for medium changes.
Veratridine (2-100 µM), 50 µM veratridine plus 1 µM
tetrodotoxin (TTX), or 2 mM CCh were added as described in
RESULTS (all from Sigma).
Percoll purification of adrenal cells.
For separation of adrenocortical from chromaffin cells, dissociated
cells were washed and resuspended in modified frog Ringer solution that
contained bovine serum albumin (BSA), low calcium, and no magnesium
(114 mM NaCl, 2 mM KCl, 6.2 mM NaHCO3, 50 µM CaCl2, 2.5 mg/ml BSA, 5.5 mM glucose, 1 × 105 U/l penicillin, 100 mg/l streptomycin, and 2.5 mg/l
amphotericin, pH 7.3, saturated with air). The cell suspension
was filtered through a 53-µm Spectra/Mesh nylon filter (Spectrum,
Houston, TX) and then layered on top of a discontinuous Percoll
gradient (22) modified for frog. Percoll (Pharmacia
Biotech, Uppsala, Sweden) was adjusted to pH 7.3 and 230 mmol/kg
osmolality, diluted to 1.025 g/ml, 1.055 g/ml, and 1.085 g/ml using the
modified Ringer (vide supra), and underlayered in 3-ml
increments beneath modified Ringer solution in 15-ml polypropylene
conical tubes (Corning, Cambridge, MA). Cells from no more than three
frogs were applied to each column. The gradient was centrifuged (600 g, 15 min), and the adrenocortical cell fraction located at
the 1.025/1.055-g/ml interface and the chromaffin plus adrenocortical
cell fraction at the 1.055/1.085-g/ml interface were collected and
washed in modified Ringer. The cells were cultured in 24-well plates
(Costar, Cambridge, MA) or 35-mm culture dishes (Falcon Plastics) as
outlined above. The purity of each fraction was confirmed by
identification of cell types with phase-contrast microscopy and
immunocytochemistry for P450 11-hydroxylase and tyrosine hydroxylase
(31).
Immunocytochemistry.
In initial experiments, we found that 2-100 µM veratridine
induced a dose-dependent alteration in neuronal morphology with no
toxicity, as assessed by morphology and cell number; subsequently, 50 µM was used in all experiments. In experiments on the effect of
activation on chromaffin cells, chromaffin cells were depolarized with
50 µM veratridine for 24, 48, 72, or 96 h (see Fig.
2A) and fixed in 2.6% paraformaldehyde in 0.067 M phosphate
buffer, pH 7.4, on day 7 for immunocytochemistry
(31). Chromaffin cells were identified and characterized
using simultaneous immunostaining for tyrosine hydroxylase (1:1,000;
Eugene Tech International, Ridgefield, NJ) and the neuronal marker
linc (undiluted; Developmental Studies Hybridoma Bank,
maintained by Dept. of Pharmacology and Molecular Sciences, Johns
Hopkins Univ. School of Medicine, Baltimore, MD and Dept. of Biological
Sciences, Univ. of Iowa, Iowa City, IA); adrenocortical cells were
identified by histochemistry of 3-hydroxysteroid dehydrogenase or by
immunocytochemistry for P450 11
-hydroxylase (1:1,000; gift from Dr.
Mitsuhiro Okamoto) as described previously (31). Primary
antibodies were visualized using CY3-conjugated anti-rabbit IgG
(1:2,000; Jackson ImmunoResearch, West Grove, PA) and FITC-conjugated
anti-mouse IgG (1:1,000; Boehringer Mannheim). Parameters used to
assess chromaffin morphology included neurite number, neurite length,
number of branches per neurite (measured as the maximum number per
neurite on each cell), and relative intensity (scale of 1 to 4) of
tyrosine hydroxylase immunostaining measured on more than two
coverslips per treatment and more than 50 cells per coverslip. The data
were analyzed by analysis of variance followed by Fisher's protected
least-significant differences test for multiple comparisons between
groups. The percentage of immunoreactive chromaffin cells overlapping
or directly adjacent to adrenocortical cells was also determined and
analyzed by statistical methods for comparing two binomial populations.
Time-lapse video microscopy. The dynamic cellular interactions of chromaffin and adrenocortical cells were recorded with time-lapse video microscopy. Cocultures or Percoll-purified adrenocortical cells grown in 35-mm dishes were examined for up to 48 h under phase-contrast microscopy with a Nikon Diaphot inverted microscope controlled by an electronic timer to minimize exposure to light. Images were collected at 15- to 60-min intervals using a Sony charge-coupled device video camera [Quick Capture frame grabber board (Data Translation) on a Power Macintosh 7100/66 computer] and analyzed using the public domain NIH Image program version 1.61 (developed at the U.S. National Institutes of Health and available on the Internet at http://rsb. info.nih.gov/nih-image/). Time-lapse microscopy of identified adrenocortical and chromaffin cells (31) was first carried out in unstimulated (24 h) conditions followed by stimulated (50 µM veratridine, 24 h) conditions, thus controlling for individual variation in responsiveness to veratridine treatment. To control for sodium channel-related specificity of veratridine stimulation, another set of cultures was recorded in the presence of 2 µM TTX plus 50 µM veratridine (24 h) followed by veratridine alone (50 µM for an additional 24 h). The entire sequences of images were used for following individual identified cells in Figs. 3, 5, and 6; however, only frames from representative or greater intervals are shown.
HPLC analysis of catecholamines and indolamines. The effect of veratridine-induced depolarization on catecholamine and indolamine secretion was determined by HPLC (high-performance liquid chromatography; BioAnalytical Systems, West Lafayette, IN). Medium was collected every 24 h from untreated and 50 µM veratridine-treated cultures and immediately frozen. Epinephrine, norepinephrine, and the internal standard, 3,4-dihydroxybenzylamine (1.2 ng/ml), were extracted by adsorption to aluminum oxide; analysis of serotonin and homovanillic acid was performed on unextracted medium. The catecholamines and serotonin were separated by reverse-phase HPLC with a C18 column maintained at 37°C using mobile phase, comprising 8% acetonitrile and 92% 0.15 M monochloroacetate buffer, pH 3.0, with 0.86 mM sodium octyl sulfate and 0.7 mM disodium EDTA, and measured by electrochemical detection.
Aldosterone and corticosterone.
Following 90-min stimulation with 50 µM veratridine and unstimulated
controls, the medium was collected and immediately frozen for
subsequent radioimmunoassay of corticosterone (ICN Biomedicals, Costa
Mesa, CA) and aldosterone (Coat-A-Count; Diagnostic Products, Los
Angeles, CA) content. The number of 11-hydroxylase immunoreactive adrenocortical cells was counted in three fields and extrapolated to
estimate the total number per well. The Student's t-test
was used for comparison of basal and stimulated cultures.
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RESULTS |
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Direct effects of veratridine on chromaffin and adrenocortical cell secretion. Adrenocortical cells were purified on a Percoll gradient to verify that veratridine did not directly affect steroid secretion. In purified cultures, 24-h veratridine treatment resulted in no significant increase in corticosterone secretion compared with untreated controls (control: 397 ± 47 pg/1,000 cells; veratridine: 518 ± 92 pg/1,000 cells; n = 4), whereas in cocultures it increased secretion approximately sevenfold.
In another set of experiments, we determined the effect of veratridine activation on chromaffin cell secretion. Veratridine significantly increased the secretion of norepinephrine (control: 8 ± 1 ng · 1,000 cellsMorphological effects of chromaffin cell activation.
Chromaffin cell activation with 50 µM veratridine
dramatically enhanced neuronal morphology (Fig.
1). Veratridine treatment of cocultures
for 24, 48, 72, or 96 h (see Fig.
2A) resulted in time-dependent
changes in chromaffin cell morphology, including increased
1) number of neurites per chromaffin cell, 2)
neurite length, 3) number of branches per neurite, and
4) tyrosine hydroxylase immunoreactivity (Fig. 2,
B-E). Chromaffin cell activation for >48 h (Groups IV
and V) also significantly increased the number of contacts between
chromaffin and adrenocortical cells (Fig. 2F). It is
noteworthy that 48-h veratridine treatment immediately before fixation
(Group VI) resulted in greater enhancement of neuronal morphology
compared with those in which veratridine-induced activation had ceased
for 3 days (Group II), indicating reversibility and plasticity of the
cells.
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Time-lapse microscopy.
Time-lapse video microscopy of cocultures was used to document the
dynamic interactions between chromaffin and adrenocortical cells under
basal and stimulated conditions. Although chromaffin cells in coculture
routinely extended neurites (Fig.
3A), these seldom developed
into long neurites with growth cones, as observed with prolonged
activation (Fig. 3B and Fig.
4). The pattern of neurite outgrowth in
unstimulated conditions often showed repetitive extension and
retraction, resulting in little overall neurite change. In contrast, in
veratridine-treated cultures, neurites established growth cones and
longer neurites, often forming contacts with adrenocortical cells (Fig.
3B and Fig. 4, A and B). The effect of
veratridine stimulation was already evident within 30 min, and by
24 h, chromaffin cells established numerous contacts with adrenocortical cells and showed significant neurite outgrowth, growth
cones, varicosities, and round soma. Figure 3A shows a characteristic unstimulated chromaffin cell that began with a neurite
extended to an unidentified nonneuronal cell. The neurite was retracted
after 2 h and remained so throughout the rest of the 18 h of
observation. Within 3 h of veratridine treatment (Fig. 3B), this same chromaffin cell extended neurites that
developed into complex processes and established contacts with
adrenocortical cells (Fig. 3B and Fig. 4B).
Although the distance between the chromaffin cell soma and the
adrenocortical cell labeled "2" eventually increased after 12 h, contact was maintained by the neurite (see Fig. 4B).
Neurite outgrowth in the presence of veratridine plus TTX, which
antagonizes the effects of veratridine on sodium channels, was similar
to that of control cultures (Fig.
5A). TTX
reversibly blocked the effects of veratridine, as shown by the neurite
outgrowth and branching that occurred during the 24 h following
removal of TTX (Fig. 5B).
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Short-term effects of chromaffin cell activation.
Because ACTH-stimulated steroidogenesis was correlated with a twofold
increase in the percentage of adrenocortical cells expressing the Fos
protein, we used Fos expression to determine whether chromaffin cell
stimulation of adrenocortical cell function occurred at the transcriptional level. In two separate experiments, veratridine and CCh
stimulation of chromaffin cells resulted in an increase in the number
of adrenocortical cells expressing Fos within 60-90 min after
stimulation. In the first experiment, CCh and veratridine stimulation
resulted in significant increases in the number of adrenocortical cells
expressing Fos (P < 0.01, compared with control), with
the greatest effect evident at 60 and 90 min after CCh (Fig. 7A; 37% increase vs.
untreated) and veratridine (Fig. 7B; 25% increase),
respectively. We suspect that the relatively high basal (unstimulated
control) expression of Fos in this experiment was due to stimulation by
basal catecholamine secretion (see Direct effects of veratridine
on chromaffin and adrenocortical cell secretion). When we
repeated this experiment, adrenocortical cells showed lower (23 ± 3%) basal (unstimulated control) expression of Fos and increased Fos
expression at 60 and 90 min following veratridine or CCh (data not
shown). Corticosteroid secretion apparently increased concomitantly
with Fos expression (corticosterone, 1.5 h; basal: 4.9 ± 0.8 pg/1,000 cells, veratridine: 13.0 ± 5.5 pg/1,000
cells; aldosterone, basal: 3.8 ± 1.5 pg/1,000 cells, veratridine:
5.3 ± 3.5 pg/1,000 cells).
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DISCUSSION |
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Chromaffin cell activation in the frog adrenal cocultures resulted in dramatic modification of chromaffin cell phenotype, including differentiation of a more neuronal morphology and increased tyrosine hydroxylase expression, both likely to facilitate the interactions between chromaffin and adrenocortical cells. Indeed, our studies show an increased number of chromaffin-adrenocortical cell contacts and increased synaptic efficacy (30) following chronic chromaffin cell activation. Veratridine-induced activation of chromaffin cells stimulated their release of norepinephrine, epinephrine, and serotonin, and, in turn, adenocortical cell release of corticosteroids. VIP and other neuropeptides, expressed by chromaffin cells in the cocultures, are also likely to be released with depolarization. Norepinephrine, epinephrine, serotonin, and VIP have all been shown to increase corticosteroid secretion (10-12, 16, 17, 25, 38) and, thus are likely to mediate corticosterone secretion following chromaffin cell activation in coculture (30).
Depolarization-induced modifications of neuronal phenotypes have previously been demonstrated for several different types of neurons, including chromaffin cells, and are speculated to have broad implications for neural development (26, 35) and plasticity. The effect of chronic depolarization on chromaffin cells in the frog adrenal cell cocultures was comparable to that reported in rat chromaffin cells (35). Similar to the frog (31), rat chromaffin cell neurite outgrowth was unaffected by dexamethasone (13, 36) or by CCh, which causes only transient activation of chromaffin cells (5). Chromaffin cell depolarization inhibits the increase in adrenal leucine-enkephalin and preproenkephalin mRNA that occurs following denervation (23) and induces the synthesis of tyrosine hydroxylase (29), suggesting that trans-synaptic activity can differentially regulate neurotransmitter and neuropeptide expression. Our studies provide further evidence that depolarization, in addition to environmental factors such as NGF and glucocorticoids (1, 13), affects chromaffin cell phenotype.
The physiological relevance of the adrenal cortical-chromaffin cell coculture model is underscored by the evidence for reciprocal interactions between chromaffin and adrenocortical cells. The possible presence of an adrenocortical neurotrophic factor that affects chromaffin cell growth and phenotype is indicated by the extension of chromaffin cell neurites to adrenocortical cells and the enhanced neurite outgrowth that occurs following ACTH stimulation of steroidogenesis (31). The nature of this neurotrophic factor is as yet unidentified, but may be growth factors, adhesive proteins, and/or extracellular matrix proteins. This neurotrophic effect is likely to be effective in vivo and important during development and in the regulation of adrenocortical cell steroidogenesis and proliferation. Accordingly, we have recently demonstrated that dietary sodium restriction stimulates expansion of the distribution of VIP-containing adrenocortical nerve fibers concomitantly with expansion of the zona glomerulosa and is possibly mediated by a trophic effect of the zona glomerulosa cells (20). Basic fibroblast growth factors, previously shown to be present in glomerulosa cells (2) and to be neurotrophic for chromaffin cells (33), may mediate this effect.
Chromaffin cells also modulate adrenocortical cell organization and function, as shown by the migration of adrenocortical cells toward chromaffin cells and their effect on adrenocortical Fos expression and corticosterone secretion. The increased expression of the Fos protein indicates that adrenocortical cells are affected at the transcriptional level and may alter adrenocortical cell phenotype. Indeed, ACTH stimulation, also shown to increase Fos expression (40; unpublished observations), stimulates the expression of steroidogenic enzymes and thereby exerts a long-term effect on steroidogenic capability (32). Our observations of the migration of adrenocortical cells also have possible implications for the histogenesis of the adrenal cortex. A current well-supported hypothesis proposes that adrenocortical cells of the mammalian adrenal gland proliferate in the outer zone and move inward either by migration and/or mitotic pressure, with cells undergoing the phenotypic changes characteristic for each zone, with apoptosis finally occurring in the innermost zone (3). Whereas chemotactic assays have previously ascertained adrenocortical cell migration (28), our studies directly demonstrate adrenocortical cell migration using time-lapse microscopy. Laminin is a chemotactic factor for bovine fasciculata cells; however, its uniform distribution throughout the adrenal cortex suggests that it is likely not the attractant driving adrenocortical cell migration (28). Our observations of cell migration of adrenocortical cells grown on a laminin substrate support this; yet, the migration rate of adrenocortical cells in cocultures is greater than that of purified adrenocortical cells. The directed movement toward chromaffin cells in coculture, in contrast to the random movement of purified adrenocortical cells, leads us to speculate that the adrenocortical cells migrate toward a trophic stimulus expressed in the adrenal medulla.
In conclusion, our results provide further evidence for the reciprocal interactions between chromaffin and adrenocortical cells that affect differentiation and modulate corticosteroidogenesis. Furthermore, adrenal neuronal and adrenocortical plasticity have significant implications during development and during acute physiological challenges such that the cohesive function of the adrenal gland is optimized.
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ACKNOWLEDGEMENTS |
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The 11-hydroxylase antibody was provided by Dr. Mitsuhiro
Okamoto, Department of Molecular Physiological Chemistry, Osaka University Medical School. The linc monoclonal antibody
developed by M. Constantine-Paton was obtained from the Developmental
Studies Hybridoma Bank maintained by the Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, and the Department of Biological Sciences, University of
Iowa, Iowa City, IA, under National Institute of Child Health and Human
Development contract NO1-HD-23144.
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FOOTNOTES |
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This work was done during the tenure of a student award from the American Heart Association, Illinois Affiliate, and was supported by National Science Foundation Integrative Biology and Neuroscience Grant 97-29344.
Address for reprint requests and other correspondence: M. A. Holzwarth, 524 Burrill Hall, 407 S. Goodwin Ave., Univ. of Illinois, Urbana, IL 61801 (E-mail: holzwart{at}uiuc.edu).
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.
Received 16 February 1999; accepted in final form 21 July 2000.
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