Human Molecular Genetics, 2001, Vol. 10, No. 26 2973-2981
© 2001 Oxford University Press
Ectodysplasin-A1 is sufficient to rescue both hair growth and sweat glands in Tabby mice
J. C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USA and 1Laboratory of Genetics, National Institute on Aging, Baltimore, MD 21224, USA
Received September 10, 2001; Revised and Accepted October 29, 2001.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Mutations in the human ectodysplasin-A (EDA) are responsible for the most common form of the ectodermal dysplasia and the defective orthologous gene in mice produces the tabby phenotype, suggesting its vital role in the development of hair, sweat glands and teeth. Among several EDA splice isoforms, the most common and the longest EDA splice isoforms, EDA-A1 and EDA-A2, differing by only two amino acids, activate NF-
B-promoted transcription by binding to distinct receptors, EDAR and XEDAR. The extent to which any particular isoform is sufficient for the formation of hair, sweat glands or teeth has remained unclear. Here we report that transgenic expression of the mouse EDA-A1 isoform in tabby (EDA-less) males rescued development of several skin appendages. The transgenic tabby mice showed almost complete restoration of hair growth, dermal ridges, sweat glands and molars. The number of hair follicles in the transgenic mice is the same as in wild-type; though the development of follicles and associated glands varies from indistinguishable from wild-type to smaller and/or only partially formed. These results suggest that the other EDA isoforms may not be absolutely required for skin appendage formation, but consistent with distinctive temporal and spatial expression of the EDA-A2 isoform, are likely required for appropriate timing and completeness of development. Our data provide the first direct physiological evidence that EDA-A1 is a key regulator of hair follicle and sweat gland initiation; its soluble ligand form could aid in deriving therapeutic reagents for conditions affecting hair and sweat gland formation. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The toothless men of Sind, described by Charles Darwin in 1875, the large cohort described in the 1938 WPA guide on Mississippi as ‘Whitaker Negroes’, and the ‘tabby’ mouse, all have mutations in the same X-linked gene, and all show inherited anomalies in hair, sweat gland, and tooth formation (1–3). We have cloned the human EDA gene and the tabby (Ta) mouse counterpart, and characterized the molecular defects of the gene in patients with ectodysplasin-A (EDA) and in mice with tabby alleles (4–6). The gene encodes a transmembrane protein, EDA, a member of the tumor necrosis factor ligand superfamily that also contains an extracellular triple helix-forming collagenous domain (6–8).
Expression analysis and immunohistochemistry confirms the localization of EDA in the membranes of keratinocytes and skin appendages, and its absence in tabby mice (6–10). Clinical features of EDA further support the tabby mouse as a good model to study the pathophysiology of this disorder. Humans lacking EDA gene function have sparse or absent scalp hair, an inability to sweat due to a lack of eccrine sweat glands and abnormal or missing teeth. In a comparable way, homozygous female (Ta/Ta) and hemizygous male (Ta/Y) tabby mice have fewer hair follicles: lacking zigzag and guard hair, two of the four hair types in wild-type mice (11); lack sweat glands and dermal ridges (12); and show defective tooth development (10,13).
The underlying early steps in skin appendage development involve inductive interactions between mesenchyme and epithelium that are controlled by several signaling networks. Recent studies implicate defective nuclear factor-B (NF-B) signaling in genetic disorders that include ectodermal dysplasias arising from lesions in EDA or EDA receptors (14–17). The two longest of several isoforms of EDA, EDA-A1 and EDA-A2, differ only by an insertion of two amino acids in the extracellular domain, but this results in binding of EDA-A1 (391 amino acids) selectively to the ‘EDAR’ receptor, whereas EDA-A2 (389 amino acids) binds only to the related but distinct ‘XEDAR’ receptor to activate NF-B (14). As expected, mutations in the EDAR gene also produce an EDA-like phenotype in human, and mutation of the orthologous gene in mouse produces the downless (dl) phenotype that is similar to the tabby mouse (18,19). Functional complementation using three overlapping mouse yeast artificial clones from the downless critical region restored the mutant phenotypes in the transgenic downless mice and suggested that one YAC clone likely contained the putative downless gene (20).
The range of defects reinforces the inference that EDA has a critical role in the primary initiation stage of skin appendage development. However, the relative function of the various EDA isoforms is unknown. The question of whether all of them are required in cooperation to produce each type of appendage, or whether they are assigned more or less specifically to affect development of one or another appendage is particularly intriguing. To address this question, we have studied the consequences of EDA-A1 expression in vivo in the mouse model, by generating a line of tabby transgenic mice bearing mouse EDA-A1 cDNA. Expression of the EDA-A1 isoform in tabby males resulted in restored hair growth, dermal ridges and sweat glands, as well as a positive effect on tooth development. These results indicate that EDA-A1 possesses the minimal required information for the initiation and growth of several skin appendages and other isoforms are likely required for appropriate timing and completeness of development.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Generation of EDA-A1 transgenic mice
We have generated a line of tabby males (Ta/Y<6J>) containing a transgene that encodes the EDA-A1 isoform. The tabby strain contains a single base deletion in exon 1, an exon common to all EDA/Ta isoforms (6). The deletion results in a frame-shift that produces truncated protein. To mimic the naturally ubiquitous expression of the longest isoform, EDA-A1, in vivo, transgenic A1 was supplied under the control of the widely expressed human cytomegalovirus (CMV) promoter (Fig. 1A). The construct was transferred into a C57BL/6J background (the genetic background of Tabby<6J>) and gene passage/fertility in progeny was confirmed (Fig. 1). Founders carrying the transgene revealed the expression of transgenic EDA-A1 mRNA in many organs including skin (not shown). Tabby males carrying the transgene (Fig. 1B) were confirmed with tests for the endogenous gene (Fig. 1C), transgene (Fig. 1D) and Ta<6J> mutation (Fig. 1E). Real-time RT–PCR analysis further confirmed the comparable expression level of EDA-A1 in tabby transgenic and wild-type males (Fig. 1F). As expected, the level of endogenous transcript in wild-type males and in tabby males that carry a point mutation (see above) affecting only translation and not transcription was similar to the level of transgene-specific transcript in transgenic tabby males. Male mice carrying the Ta<6J> mutant allele and transgene were studied further.
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Hair growth in tabby transgenic mice
EDA-A1 transgenic mice were indistinguishable from their wild-type littermates and showed no gross phenotypic abnormalities. As reported in original descriptions, tabby females are larger than wild-type (3). In contrast, Ta/Y mice are consistently somewhat smaller than wild-type, and require liquid food for early survival. Ta/Y (Tg) mice regain the size and vigor of wild-type (Fig. 2).
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Ta/Y mice have a characteristic yellowish, slightly scrawny coat, correlated with the absence of the guard and zigzag hair types (Fig. 2B). The Ta/Y (Tg) mice show the restoration of normal coat color (Fig. 2C). Luxuriant hair growth behind the ears of wild-type mice (Fig. 2A and D) is missing in tabby males, leaving a discrete bald patch (Fig. 2E). The EDA-A1 transgene restores wild-type hair growth (Fig. 2C and F), along with the generalized restoration of brownish, smooth coat hair. The restoration of hair growth in Ta/Y (Tg) mice can also be seen in the body trunk (not shown).
Sweat gland formation and development of dermal ridges in transgenic tabby mice
In wild-type mice, digits and footpads show an organized structure of parallel dermal ridges, associated with the development of sweat glands. Scanning electron microscopy reveals that the ridges in wild-type (+/Y) are either absent or underdeveloped in Ta/Y mice, with no apparent organized rows (Fig. 3). In the Ta/Y (Tg) animals, the structure of dermal ridges is restored, indistinguishable from that in wild-type (Fig. 3A).
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Comparably complete restoration of sweat glands is indicated by sweat tests with the starch-iodine reaction (Fig. 3B). In human EDA patients, the reaction reveals the presence or absence of sweat glands in the skin. In sweat tests on footpads, where the preponderance of mouse sweat glands are concentrated, wild-type and Ta/Y (Tg) mice demonstrated sweating, whereas Ta/Y male mice showed total anhidrosis. Three to 5 min after starch/iodine is applied to wild-type footpads, sweat glands show the characteristic punctate surface pattern; by 10–15 min, the footpad is totally darkened. In contrast, Tabby mouse (Ta/Y) footpads show no reaction even after 15 min. Like dermal ridges, the wild-type phenotypic sweat tests are completely restored in Ta/Y (Tg) mice. For example, we found a range of 44–52 sweat pores (black dots) in five different photographs of footpad segments from two tabby transgenic mice, with a mean of 47.8 and a SD of 3.34. This is somewhat lower but comparable to the observed range of 45–67, with a mean of 52.2 and a SD of 9.0, in an equivalent number of wild-type footpad sections from three wild-type mice. Intensity of the starch/iodine color reaction varies in photographs taken at different angles, but the pattern and the timing of the development of color are indistinguishable in tabby transgenic and wild-type.
Restoration of tail skin texture and hair by EDA-A1 expression
Tabby mice (Ta/Y) show a distinctive tail phenotype compared to wild-type. Scanning electron microscopy (Fig. 4) shows an organized, ‘shingled’ appearance of corneocytes on the skin surface in wild-type (+/Y) mice, with hair extending parallel to the tail from follicles along its length. Ta/Y mouse tails show loosened corneocytes and no hair. The layered appearance of the tail skin is largely restored in the Ta/Y (Tg) mice, and levels of hair comparable to wild-type were also restored. For example, in tabby transgenic animals the number of hairs ranged from 26–28 in three instances (scored in 95 x 150 mm scanning electron microscopy pictures photographed at higher magnification) compared to 27–35 hairs in equivalent segments of three wild-type males. However, qualitatively, the physical appearance of the tail hairs was somewhat variable in the tabby transgenic male mice, with some hairs indistinguishable from wild-type and others rather thinner and shorter than the more uniform hair of wild-type animals.
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These results are confirmed and extended in transverse sections of tails from the same animals (Fig. 5). At the dermal layer, wild-type shows trios of hair follicles and their associated sebaceous glands. Ta/Y mice show neither hair follicles nor sebaceous glands. The number of hairs present in tabby transgenic animals and in wild-type males were again scored by counting the number of hair follicles in three to five transverse sections of tails from three tabby transgenic males and three wild-type males. The number of hair follicles in the wild-type sections was consistently 36, compared to a range of 30–36 hair follicles per equivalent tail section in tabby transgenic sections. Furthermore, in the Ta/Y (Tg) mice, although wild-type follicle numbers are restored (approximately 12 trios per tail perimeter), the development of the individual follicles and associated glands is variable, with some looking as complete as wild-type and others smaller and/or only partially formed (Fig. 5D–F).
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EDA-A1 and tooth development
The effect of tabby mutations on tooth development is variable, with penetrance affected by the background genotype (13). Nevertheless, qualitative changes can be seen. Mice usually have one incisor and three molars in each half of the maxilla and mandible. In tabby males, molars were rather smaller than wild-type, and maxillar molars also showed fewer and more shallow, ‘flattened’ cusps. Third molars were absent in both mandible halves and incisors in the mandible were frequently smaller. In the transgenic tabby males, molars were still generally smaller, but the wild-type number of three molars were noted in both halves of the mandible (Fig. 6 and not shown), and incisors were restored to wild-type size (not shown).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The reconstitution of multiple tabby deficits by EDA-A1 supports its primacy in skin appendage formation (Fig. 7). It is inferred to act at an early stage, during the mesenchyme/ectodermal interactions that initiate appendage formation.
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The pathway (Fig. 7) progresses through EDAR, the receptor for A1. EDA-A1 action is currently thought to start with proteolytic cleavage by a furin-like protease, which releases a soluble trimeric TNF-like ectodomain that binds to the TNF receptor EDAR (9,21) (Fig. 7). Consistent with this formulation, mice mutant in EDAR (‘downless’) have a phenotype very similar to tabby and EDAR has been shown to act through NF-
B (14,15). It is notable that although components of that pathway are also involved in other developmental processes, mutations in NF-B or IB result in disorders that markedly affect skin development (22–24).
This is further supported by the observation that mice with suppressed NF-B activity revealed defective early morphogenesis of hair follicles, exocrine glands and teeth, identical to EDA (tabby) and EDAR (downless) mutant mice (25). Therefore, EDA-A1 would have much of its effect through the downstream transcription of genes involved in the specification of the various appendages (Fig. 7). Additionally, it is important to note that a patient with an EDA mutation affecting an intron splice donor site, predicted to eliminate specifically the EDA-A1 but not the EDA-A2 isoform, is fully affected with X-linked EDA (26). This further suggests the primary involvement of EDA-A1 in skin appendage development, complementary to the results reported here.
Additional participants in the regulatory pathway include regulators of EDA formation, additional interactions of EDA-A1, other isoforms of EDA and additional signaling pathways. For the transcription of the EDA gene, for example, the Wnt pathway is required (M.C.Durmowicz et al., manuscript in preparation). And EDA-A1 itself, without a proteolytic cleavage step, may interact both with molecules on the cell that produces it and on neighboring cells (9,21). Particularly suggestive is another extracellular segment of the molecule in which mutations result in EDA: a collagen-like domain that may interact with cell matrix components (27).
The variable development of tail hair follicles and incompleteness of complete structural restoration of the molars of the tabby mouse with EDA-A1 is probably not attributable to insufficient expression, because the level of EDA-A1 expressed from the transgene is very comparable to endogenous EDA-A1 levels. Furthermore, additional EDA-A1, expressed from the transgene in a wild-type background, has no detectable effect on skin appendages, so that the wild-type level likely saturates the need. This also suggests that EDA-A1 expression from a CMV promoter throughout development and in all tissues is apparently not damaging, though this possibility is difficult to exclude completely. Alternatively, use of a Ta promoter with its regulatory elements could resolve some of these problems, as it might mimic the timing and distribution of expression as in wild-type animals. The fact that wild-type levels of transgenic A1 incompletely rescue phenotypes that are also seen in downless mice indicates that the EDAR receptor may not be fully activated in these transgenic mice. Most likely additional factors, possibly other EDA-A isoforms, act with or through EDAR. Alternatively, EDA-A2/XEDAR signaling may also play a secondary role. One clue may come from the distinctive temporal and spatial expression of XEDAR later in development (E16/E17 stages) than EDAR at E14, which could speculatively be involved in modulation of the NF-B pathway to further facilitate the maturation of appendages started under EDAR control (14). EDA isoforms B and C, present in both human and mouse, are also expressed differentially during development (unpublished data), but lack the collagen-like and TNF-ligand regions of EDA, so that their contributions would necessarily be independent of receptors for A1 and A2.
As for other pathways, EGF has been shown to compensate in part for the tabby lesion, and the disruption of EGFR also leads to other epithelial defects (Fig. 7) that likely operate through transcription factors, possibly NF-B (28–31). In addition, several molecules have been reported to have critical functions in mesenchyme/epithelium interactions that produce skin appendages. They include BMP-4/Noggin, fibroblast growth factor-7 (FGF-7), and FGF-10, derived from the mesenchyme, and additional actions of LEF1/ß-catenin, sonic hedgehog (SHH) and FOXN1, the winged helix transcription factor, derived from the epithelium (10,32–38). However, information about the involvement of these factors is generally incomplete. For example, FGF-10 has thus far been specifically identified only as involved in tooth development (10), and LEF1/ß-catenin have been implicated in early initiation stages and the cycling of hair follicles (34,35,38). Furthermore, unlike ectodysplasin, which displays mainly skin appendage-specific effects, these signal molecules play major roles in the development of multiple organ systems and general developmental patterning. Thus, transgenic expression or deletion of any of these molecules can result in more severe and varied defects.
It is currently unclear whether other pathways are complementary or parallel to EDA signaling, or whether they converge at a downstream point. To analyze the regulatory network more completely, we are beginning to study transgenic tabby mouse lines bearing each of the major EDA isoforms under the control of a tetracycline-inducible promoter. These animals provide the opportunity to turn on isoforms singly or in combination at different times and at graded levels during mouse fetal development. Thus, the degree of overlap of their effects, and any trophic role, can be correlated with changes in gene expression profiling. But to a first approximation, EDA-A1 is sufficient for hair follicle and sweat gland formation, and in its soluble ligand form, could provide a possible therapeutic target for the correction of problems in hair and other skin appendage development.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Generation of transgenic mice
A 2.35 kb NcoI fragment of mouse EDA-A1 cDNA (GeneBank accession no. AFO16628), containing the entire coding region and 1162 nt of the 3'-UTR, was blunt-ended, cloned into SmaI-digested pCI-neo vector (Promega, Madison, WI), and confirmed by sequencing. A linear BglII–MamI fragment (CMV promoter to SV40 polyA site) was resuspended in 8 mM Tris–HCl pH 7.5, 0.1 mM EDTA and microinjected into pronuclei of one-cell inbred C57BL/6 mouse embryos. Those were then surgically implanted into ‘pseudo-pregnant’ female mice, and progeny were genotyped for the transgene by PCR and Southern blot analysis. Potential founders were mated to C57BL/6 mice to identify those passing the transgene. Expression of the transgene was checked by RT–PCR in RNA isolated from liver, kidneys, and skin of at least two mice for each line. From each of two independent lines, transgene-positive males were mated with heterozygous tabby females (C57BL/6J-Aw-J-Ta6J strain; Jackson Laboratory, Bar Harbor, ME). Transgene-carrying tabby female and male mice were identified by PCR, and the tabby females were mated with hemizygous tabby males to generate additional tabby males carrying the transgene. Mice were usually weaned at 3–4 weeks.
DNA genotyping and transgene detection
Progeny from each cross were analyzed by PCR for the transgene using two primer sets: Moee1F, 5'-GCTACCTAGAGTTGCGGTCCG-3' and Moee2R, 5'-CCCACCTGGCCCTCCTGGTCCTCA-3', which amplify a 330 bp product from the transgene DNA only; and Br2F, 5'-CCCACCTGGCCCTCCTGGTCCTCA-3' and Moee3B, 5'-CAGATGCACAGCTGGCT-3', which amplify a 106 bp product from transgene and a 2.2 kb product from genomic DNA. Cycling conditions included: denaturation at 95°C for 3 min, 35 cycles of 95°C for 30 s, 60°C (65°C for Br2F/Moee3B) for 30 s, 72°C for 30 s (2.5 min for Br2F/Moee3B), and a final extension at 72°C for 7–10 min. Results were confirmed by standard Southern hybridization in founder mice. In subsequent breeding, each pup was analyzed for: (i) the presence of endogenous EDA genomic DNA using primer Moex3'-1: 5'-AACAGCAGCCTTTGGACCGG-3' from exon 1 and primer M7252P2: 5'-AACCTGACCTGGACAACCTCT-3' from intron 1 (230 bp product); (ii) the transgene using primers Moee1F and Moee2R; (iii) the tabby mutation with the Incorporation PCR SSCP method (39). A 387 bp product was amplified in the presence of [32P]dCTP with Moee1F and M7252P2, digested with BglI and analyzed for tabby and normal alleles on a 0.5x MDE gel (BioWhittaker Molecular Applications, Rockland, ME).
RNA isolation and analysis
Tissues were homogenized and total RNA isolated in Trizol reagent (Life Technologies, Rockville, MD). RT–PCR was carried out with GeneAmp PCR Kit (Applied Biosystems, Foster City, CA), using primers TaA3utr: 5'-GGAATTCCCAAACCCTACACTCCC-3' and cIneo3: 5'-GCTCGAAGCATTAACCCTCACTAAAGG-3' (200 bp product from transgene transcript only), and Br2F and Moee3B.
Real-time quantitative RT–PCR was carried out on RNA from back skin of wild-type and tabby transgenic males. Reactions were set up with TaqMan One Step RT–PCR Master Mix reagents (Applied Biosystems) and cycled according to the manufacturer’s instructions. Primer/probe sets specific for endogenous transcript (forward primer 5'-AATTTTCCATTTATTAGGCATACAATTCT-3'; reverse primer 5'-GTGCCACCGATCTTCAAACTCT-3'; TaqMan probe 5'-[6FAM]CAGATGGTTAAACTGGATAACCTCCAAAAGCCC-3') and transgene transcript (forward primer 5'-CAGGAAATGTTGTCCACTTTTGTT-3'; reverse primer 5'-TGTCCAAACTCATCAATGTATCTTATCA-3'; TaqMan probe 5'-[6FAM]CTCTTATCTGAAAGAGCAGCAGGCCATG-3') were designed by Primer Express software (Applied Biosystems) and the standard curve method was used to assess expression levels of transcript relative to a GAPDH control in each sample.
Iodine sweat test
For the iodine sweat test (12), the mouse was restrained and the plantar surface of a rear paw painted with iodine/alcohol (2 g iodine/100 ml ethanol). Once dry, paw surfaces were covered in starch-oil suspension (100 g starch/100 ml castor oil). Fine black dots revealed functioning sweat gland pores.
Analysis of adult tooth phenotype
Adult jaws (maxilla and mandible) were dissected out and cleaned. Teeth embedded in jaws were viewed and photographed using a Zeiss Stemi 2000-C microscope.
Scanning electron microscopy
Each sample was placed into 3.5% glutaraldehyde buffered with Plumel’s cacodylate pH 7.4 (EMS, Electron Microscopy Science, Fort Washington, PA) for 4 h. Samples were rinsed in buffer and dehydrated through a graded series of ethanol (50, 70, 80 and 90%, for 15 min, 95% two rinses for 15 min each, and 100% two rinses for 30 min each). Dehydrated samples were critical point dried, mounted and coated with gold using Hummer X Sputter Coater by Anatech (Springfield, VA), thickness 
300 Å. Samples were viewed using a Hitachi 3500N scanning electron microscope. Images were collected digitally and stored.
Histology
Fresh tissues harvested from control and experimental animals were fixed in 3.0% glutaraldehyde in 0.1 M Milonig’s phosphate buffer. Fixed samples were subjected to dehydration by immersion in graded alcohol solutions (80, 90 and 100%; two baths each for 30 min/bath), xylene solution (two baths, 30 min each) and paraffin infiltration (Paraplast X-tra tissue embedding medium). Histological sections were cut at 5 µm thickness and stained using hematoxylin and eosin. Slides were viewed under an Olympus BX50 microscope.
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ACKNOWLEDGEMENTS |
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We thank Dan Rowley, Reede Cooley, Eric Douglas and Alex Billioux for technical assistance, Will Blackburn for advice and Charles E.Schwartz, Dan Longo and Roger E.Stevenson for critical reading and review of the manuscript. M.C.D. is supported by a Pharmacology Research Associate Training Award (PRAT) from the National Institute of General Medical Sciences, NIH.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +1 864 388 1806; Fax: +1 864 388 1808; Email: anand@ggc.org The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors Present address: Joan Hudson, Clemson University, Clemson, SC, USA
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