PRL-1 PTPase expression is developmentally regulated with tissue-specific patterns in epithelial tissues

Weihong Kong, Gary P. Swain, Shiuxing Li, and Robert H. Diamond

Division of Gastroenterology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6145


    ABSTRACT
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The mechanisms controlling tyrosine phosphorylation of cellular proteins are important in the regulation of many cellular processes, including development and differentiation. Protein tyrosine phosphatases (PTPases) may be as important as protein tyrosine kinases (PTKs) in these processes. PRL-1 is a distinct PTPase originally identified as an immediate-early gene in liver regeneration whose expression is associated with growth in some tissues but with differentiation in others. We now demonstrate that the PRL-1 protein is expressed during development in a number of digestive epithelial tissues. It is expressed at variable time points in the developing intestine, but its expression is limited to the developing villus enterocytes. In the gastric epithelium, PRL-1 expression in the adult is restricted to zymogen cells. PRL-1 is also expressed in the developing liver and esophagus and in the epithelia of the kidney and lung. In each of these contexts, the expression of PRL-1 is associated with terminal differentiation, suggesting that it may play a role in this important developmental process.

tyrosine phosphatase; differentiation; signal transduction


    INTRODUCTION
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

INSIGHT INTO the molecular and cellular mechanisms controlling the development and differentiation of digestive and other epithelial tissues has been increasing in recent years. However, the role of tyrosine phosphorylation and attendant signal transduction pathways in these processes requires greater elucidation. Because tyrosine phosphorylation is involved in the regulation of many cell functions, playing a critical role in the regulation of gene expression, enzymatic activity, cell cycle progression, and cellular transport and motility (12, 13, 18), it is likely that roles exist in the regulation of tissue development and differentiation as well.

Protein tyrosine phosphatases (PTPases) are as important as tyrosine kinases in regulation of important tyrosine phosphorylation signaling pathways (9, 33, 36, 40). Recent experiments indicate that some PTPases play significant roles in vertebrate development. Sokol and colleagues (34) showed that interruption of SHP2 PTPase signaling by overexpression of a dominant mutant PTPase resulted in severe posterior truncation mutations. Several receptor PTPases are of critical importance in the fetal brain, influencing cell-cell adhesion, neurite growth, axon guidance, and target cell recognition (30, 32). The receptor PTPase LAR-PTP2 was found to be highly expressed in fetal lung only at the particular point of maximal tissue differentiation when terminal bronchioles and alveolar sacs are being formed (28). In situ hybridization experiments have demonstrated that the MKP-1 PTPase is expressed in a tissue-restricted and temporal pattern during mouse development. Significant levels were found early in gut development, with mRNA detected at 10.5 days, whereas expression later in development was found to be limited to villus enterocytes (3).

We first identified the nonreceptor PTPase PRL-1 as an immediate-early growth-response gene in regenerating liver and mitogen-treated 3T3 fibroblasts (6, 23). In addition to regenerating liver, PRL-1 is expressed in skeletal muscle and brain, two terminally differentiated tissues (6). PRL-1 is also expressed significantly in intestinal epithelia, and, in contrast to the expression pattern of PRL-1 in liver, its expression is associated with cellular differentiation in the intestine. Specifically, PRL-1 is expressed in villus but not crypt enterocytes and only in differentiated Caco-2 colon carcinoma cells (8). These results suggest that PRL-1 may play different roles depending on tissue context.

To explore these issues further, we determined the expression pattern of PRL-1 during digestive tissue development. We found that PRL-1 is expressed at a number of different time points in the developing small and large intestine and that its expression in this context is associated with enterocyte differentiation. Additionally, PRL-1 is expressed in the gastric epithelium, with restriction to developing and adult zymogen cells. Furthermore, PRL-1 is expressed in the developing esophagus and liver and in the developing and adult kidney and lung.


    MATERIALS AND METHODS
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Animals. Adult and postnatal tissue samples were harvested from Sprague-Dawley rats (160-200 g; Charles River). For developmental time points, timed pregnant female Sprague-Dawley rats were obtained (Charles River). At the indicated time points, the animals were killed by cervical dislocation and the abdomen was opened. The uterine horns were identified, the cervical, oviduct, and vaginal linkages were cut, and the uterine horns were lifted clear, placed in a petri dish in PBS, and incised on the antimesoatrial side (11).

Immunohistochemistry. Tissues were removed and fixed overnight at 4°C in 4% paraformaldehyde in PBS, pH 7.4. Paraffin sections (6 µm thick) were prepared at room temperature, deparaffinized with xylene, and rehydrated in ethanol. After endogenous alkaline phosphatase activity was quenched by treating the slides in 0.2 N HCl for 15 min, the sections were blocked with avidin followed by biotin (Vector) and then further treated with protein blocking agent (Immunotech). The sections were then incubated overnight at 4°C with affinity-purified rabbit polyclonal anti-PRL-1 antibody (0.17 µg/ml) or an equivalent concentration of nonimmune rabbit IgG (Sigma) as a control. The anti-PRL-1 antibody is the same one we have used previously (6, 8). The integrity of this antibody was previously demonstrated by detection of transfected PRL-1 by Western blot and immunofluorescence studies and by the absence of staining by anti-PRL-1-depleted sera prepared from the flow-through of a PRL-1 affinity column (6). In select cases, tissues were stained with rabbit polyclonal anti-human intrinsic factor antibody (a generous gift of Dr. David Alpers). Sections were then extensively washed with PBS and incubated with biotinylated anti-rabbit antibody (Biostain) at 37°C for 30 min, followed by a 30-min incubation with avidin-biotin complex reagent (Biostain). The sections were washed in PBS and equilibrated in SMT buffer (100 mM NaCl, 50 mM MgCl2, 0.01% Tween, and 10 mM Tris, pH 9.5). The color development was performed at room temperature in SMT buffer containing nitroblue tetrazolium (NBT) and 5-bromo-4-chloro-indolyl phosphate (BCIP) (Boehringer Mannheim). Light counterstaining was done with 2% neutral red for 2 min, and the sections were then dehydrated and mounted.


    RESULTS
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

PRL-1 is expressed at multiple time points in developing intestine in association with epithelial differentiation. In Fig. 1A, serial sections of embryonic day (E)18 foregut are stained with anti-PRL-1 antibody (Fig. 1A, i and ii) and control sera (Fig. 1A, iii). In the anti-PRL-1-stained specimen, nuclei are prominently stained in some protovillus enterocytes. There is some cytoplasmic staining in other enterocytes as well. At this stage of development, the intestinal crypts are not completely formed, but it can be observed that there is no PRL-1 staining in the base of the villi. Figure 1B shows representative sections of E18 midgut (Fig. 1B, i and ii) stained with anti-PRL-1 antibodies or control sera (Fig. 1B, iii). PRL-1 staining areas are seen in the more distal enterocytes of the protovilli but not in the bases. Finally, a section from the E18 hindgut (Fig. 1C) demonstrates an absence of anti-PRL-1 staining. In contrast to the developing small intestine, it appears that PRL-1 expression begins later in the developing colon. We found that intestinal sections from E14 rats did not stain for PRL-1 in any segment, either small intestine or colon (data not shown). At this time point, villus buds have just begun to form from the preceding pseudostratified intestinal epithelium. This finding would appear to indicate that PRL-1 is not absolutely required for villus formation but, rather, it may play a role in the differentiation of these cells into mature enterocytes.


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Fig. 1.   A: fetal rat embryonic day (E)18 foregut sections stained with anti-PRL-1 antisera demonstrate that PRL-1 is expressed in both the cytoplasm and the nucleus of enterocytes in the developing villi. i: Anti-PRL-1 stained, ×100. ii: Anti-PRL-1 stained, ×600. iii: Serial section stained with control sera, ×100. B: fetal rat E18 midgut sections stained with anti-PRL-1 antisera demonstrate that PRL-1 is expressed in both the cytoplasm and the nucleus of enterocytes in the developing villi. i: Anti-PRL stained, ×100. ii: Anti-PRL-1 stained, ×600. iii: Serial section stained with control sera, ×100. C: fetal rat E18 hindgut sections stained with anti-PRL-1 antisera demonstrate that PRL-1 is not expressed in the developing epithelium at this time point; ×400.

The intestinal epithelium in rodents continues to develop and mature after birth (18, 21, 25, 26). Figure 2A shows representative serial sections of postnatal day 6 rat duodenum (Fig. 2A, i), proximal jejunum (Fig. 2A, ii), distal jejunum (Fig. 2A, iii), ileum (Fig. 2A, iv), proximal colon (Fig. 2A, v), and distal colon (Fig. 2A, vi) that are stained with the anti-PRL-1 antibody. Abundant nuclear staining is seen in the villi in the anti-PRL-1-stained small intestinal sections, whereas no anti-PRL-1 staining is observed in the developing crypts. The staining appears to become more intense and consistent as the cells progress up the villus, correlating with increased differentiation. Although there may be some cytoplasmic staining in some of these cells, the overall pattern is more clearly nuclear compared with that seen at E18. In addition, there appears to be a horizontal gradient of PRL-1 expression in the small intestine, with highest levels noted in the duodenum and jejunum and lower levels evident in the ileum. This correlates with the E18 data (Fig. 1), in which the highest levels of PRL-1 expression in the intestine were noted in the foregut and midgut. Little anti-PRL-1 staining is evident in the colon at this time point (Fig. 2A, v and vi), a pattern similar to that noted in the embryonic sections but different from that shown at later time points and in the adult.


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Fig. 2.   A: postnatal day 6 (suckling) intestinal sections stained with anti-PRL-1 antisera demonstrate that PRL-1 is expressed in the developing small intestinal villus enterocytes, predominantly in the cell nuclei, but is not expressed in the developing colon at this time point. i: Duodenum. ii: Proximal jejunum. iii: Distal jejunum. iv: Ileum. v: Proximal colon. vi: Distal colon. All images are at ×400. B: postnatal day 25 (postweaning) intestinal sections stained with anti-PRL-1 antisera demonstrate that PRL-1 is expressed in the nuclei of small intestinal villus enterocytes and in the nucleus and cytoplasm of colonocytes in the surface epithelial cuff. i: Duodenum. ii: Proximal jejunum. iii: Distal jejunum. iv: Ileum. v: Proximal colon. vi: Distal colon. All images are at ×400. C: higher-power postnatal day 25 (postweaning) intestinal sections stained with anti-PRL-1 antisera demonstrate that PRL-1 is expressed in villus enterocytes but not in goblet cells. i: Duodenum. ii: Jejunum. iii: Ileum. All images are at ×600.

By postnatal day 25 the rat has been weaned, and the intestinal epithelium has matured greatly, with deeper crypt invagination leading to an appearance that much more closely resembles that of the adult epithelium (19, 22, 26, 27). Figure 2B shows representative sections of postnatal day 25 rat duodenum (Fig. 2B, i), proximal jejunum (Fig. 2B, ii), distal jejunum (Fig. 2B, iii), and ileum (Fig. 2B, iv) that are stained with the anti-PRL-1 antibody. Anti-PRL-1 staining is clearly seen to be present in the nuclei of small intestinal villus enterocytes at this time point and absent in the crypts below. Relatively less cytoplasmic staining is seen compared with earlier developmental time points. There again appears to be a horizontal gradient of PRL-1 expression, with the strongest and most consistent staining noted in the duodenum and proximal jejunum and lesser staining seen in the ileum. Figure 2C shows higher-power views of postnatal day 25 duodenum (Fig. 2C, i), jejunum (Fig. 2C, ii), and ileum (2C, iii). These figures demonstrate that anti-PRL-1 staining is confined to the absorptive enterocytes and is not present in the goblet cells. Finally, representative sections of postnatal day 25 rat proximal colon (Fig. 2B, v) and distal colon (Fig. 2B, vi) are shown stained with the anti-PRL-1 antibody. In contrast to earlier developmental time points, there is clear evidence of PRL-1 expression in the colon at this time point. Anti-PRL-1 staining in the colon is seen most prominently in the cells of the surface epithelial cuff, which corresponds to the villi in the small intestine.

PRL-1 is expressed in zymogen cells of the stomach but not in parietal or mucus cells. The cells of the gastric glands in the adult stomach are arranged in a distinct architecture, and their characteristic morphological features permit them to be distinguished from one another (20). The zymogen cells can be distinguished by their granularity and by their location within the gland (16, 17, 20, 21). Figure 3A shows a representative section of adult stomach stained with the anti-PRL-1 antibody. A higher-power view is shown in Fig. 3B. Anti-PRL-1 staining is present only in the nuclei of granular cells in the base of the gastric glands, which are likely to be zymogen cells. However, PRL-1 expression is not observed in the well-differentiated parietal or mucus pit cells. To verify the identification of zymogen cells, Fig. 3C shows a serial section stained with anti-intrinsic factor antibody. This antibody has previously been established to stain only gastric zymogen cells in the rat (2, 31).


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Fig. 3.   Representative adult rat gastric gland sections stained with anti-PRL-1 antisera (A, ×200; B, ×600) demonstrate that PRL-1 expression in this tissue is restricted to the zymogen cells at the base of the glands. C: serial section of adult rat gastric gland stained with anti-intrinsic factor antibody to label zymogen cells; ×200. D: E14 fetal gastric epithelium stained with anti-PRL-1 antisera; ×600.

During rat development, the stomach epithelium is composed of undifferentiated cells until E18. Parietal cells can first be distinguished at E19, and zymogen cells can first be distinguished at E20. Development of these cells continues after birth, and mature zymogen cells are not present until approximately postnatal day 21 (10, 14-16). Figure 3D shows a representative section of E14 stomach stained for PRL-1. The epithelium is thin and undifferentiated at this point. Some anti-PRL-1 staining is evident in different epithelial layers. It appears that, although PRL-1 expression in the gastric epithelium is initially diffuse, it becomes more restricted as development progresses so that in the adult, PRL-1 expression is confined to the zymogen cell nuclei.

PRL-1 is expressed in a subset of cells in developing esophagus and liver. Figure 4A, i, shows a representative section of E14 esophagus stained for PRL-1. At this point in development, the cells lining the lumen in this organ are still columnar, having not yet assumed their eventual squamous morphology (1). Anti-PRL-1 staining is evident in the nuclei of some of these cells. No staining was noted in serial sections stained with control antisera (data not shown). At later developmental time points, and in the adult, when the esophageal epithelium has changed from columnar to squamous, we found no evidence of PRL-1 expression in this organ (data not shown). Thus it appears that the expression of PRL-1 in the developing gut may be restricted to cells with a columnar phenotype and is lost in the esophagus when the columnar epithelium is replaced by the squamous type.


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Fig. 4.   A: rat E14 fetal esophagus section stained with anti-PRL-1 antisera demonstrates that PRL-1 is expressed in a limited number of cells in the columnar epithelium present at this developmental time point; ×600. Rat E14 (B) and E18 (C) fetal liver sections stained with anti-PRL-1 antisera demonstrate that PRL-1 is widely expressed in both parenchymal and nonparenchymal developing hepatic cells; ×600.

Figure 4, B and C, shows representative sections of fetal liver stained with the anti-PRL-1 antibody. During development, the liver is a prominent site of hematopoiesis, a function it does not normally have in the adult (35). Accordingly, many blood cells and their precursors are seen in these sections, and these cells do not stain positively for PRL-1. Underlying this, however, prominent PRL-1 expression can be discerned in the hepatic cells. This expression is most strongly nuclear, but some degree of cytoplasmic staining is evident as well. These results are in sharp contrast to the adult liver, which does not express PRL-1 in the quiescent state but shows high levels of PRL-1 expression during the regenerative response (6, 8). Therefore, it appears that the expression pattern of PRL-1 during liver regeneration recapitulates its expression during liver development, and it is possible that PRL-1 plays similar roles in both the genesis and maintenance of this tissue.

PRL-1 is significantly expressed in kidney and lung both in adult and during development. In addition to expression in digestive tissues, staining with the anti-PRL-1 antibody was present in other epithelial tissues, both during development and in the adult. Figure 5 shows the pattern of anti-PRL-1 staining in the kidney. In the adult rat (Fig. 5A), anti-PRL-1 staining is seen to be present only in a small proportion of cells in the renal cortex. A higher-power view (Fig. 5B) shows that these are likely to be proximal tubule cells because of their brush border. The glomeruli are clearly not stained by the anti-PRL-1 antibody. PRL-1 appears to be localized to both the nuclei and the cytoplasm of these cells. This staining pattern is not seen in a section stained with control sera (Fig. 5C). A similar pattern is seen during renal development. Figure 5D shows a representative section of kidney from an E18 animal. PRL-1 staining is seen in both the nuclei and the cytoplasm of the tubular cells at this time point.


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Fig. 5.   Adult rat kidney sections stained with anti-PRL-1 antisera demonstrate that PRL-1 expression is confined to the tubular epithelial cells. A: anti-PRL-1 stained, ×100. B: anti-PRL-1 stained, ×600. C: serial section stained with control sera, ×100. D: E18 fetal rat kidney section stained with anti-PRL-1 antisera demonstrates that PRL-1 is expressed in both the nuclei and cytoplasm of the developing renal tubular epithelium; ×600.

In the adult lung, PRL-1 expression is confined to the bronchiolar epithelium. In a representative section of adult rat lung tissue stained with the anti-PRL-1 antibody (Fig. 6A), it is seen that only the cells lining the bronchioles are stained. The pneumocytes and other cells of the lung parenchyma do not appear to express PRL-1. A higher-power view (Fig. 6B) demonstrates that the PRL-1 staining pattern appears to be mostly nuclear in these bronchiolar epithelial cells, but there may be some degree of cytoplasmic staining as well. This staining pattern is not seen in sections stained with control sera (Fig. 6C). In Fig. 6D the pattern of PRL-1 expression in lung during development is shown. At E14 (Fig. 6D), the bronchiolar epithelium is not yet well formed, but anti-PRL-1 nuclear staining can be discerned. At E18 (Fig. 6E), in a pattern similar to that seen in the adult, PRL-1 expression is confined to the epithelium lining the bronchioles, and although prominent nuclear staining is apparent, there is a greater degree of cytoplasmic staining than is seen in the adult lung.


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Fig. 6.   Adult rat lung sections (A-C) stained with anti-PRL-1 antisera demonstrate that PRL-1 expression is confined to the bronchiolar epithelial cells. A: anti-PRL-1 stained, ×100. B: anti-PRL-1 stained, ×600. C: serial section stained with control sera, ×100. Fetal rat lung sections stained with anti-PRL-1 antisera (D and E) demonstrate that PRL-1 is expressed in the developing bronchiolar epithelium. D: E14 lung section stained with anti-PRL-1 antisera, ×600. E: E18 lung section stained with anti-PRL-1 antisera, ×200; inset ×600.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Our findings are consistent with the supposition that the PRL-1 PTPase may be important in the development and maintenance of differentiating epithelial tissues. It is expressed in specific terminally differentiated cells in a number of digestive organs, including the enterocytes of the small intestinal villi and colonic surface and the zymogen cells of the stomach. In the fetal counterparts of these adult tissues, as well as in the fetal (but not adult) esophagus and liver, PRL-1 is also expressed early in epithelial development, suggesting that it may play a role in guiding the development process in these tissues. In the gut, regional differences in the magnitude and timing of PRL-1 expression can be discerned, with higher and earlier levels detected in the proximal small intestine than in more distal segments and the colon. PRL-1 is also expressed, during development and in the adult, in the epithelial cells lining the pulmonary bronchioles and in the proximal tubular cells of the kidney.

In a number of mature tissues, including the epithelia of the small intestine, stomach, and lung, PRL-1 expression appears to be mostly or exclusively nuclear. However, a pattern of staining in both the nucleus and the cytoplasm was noted in the epithelia of the colon and renal tubules. In addition, a number of tissues that display a nuclear pattern of localization for PRL-1 in the adult show evidence of some cytoplasmic expression during the tissue's development. In general, it appears that the expression of PRL-1 becomes more consistently nuclear, as well as more cell type restricted, as development progresses. The function of PRL-1 may be governed in part by its subcellular localization. In this regard, it is interesting to note that PRL-1 contains a carboxy-terminal CAAX motif, which is a marker for protein prenylation. The last four amino acids CCIQ in PRL-1 point toward farnesylation as the most likely modification. It has been shown that PRL-1 can be farnesylated in vitro and is at least partly farnesylated in vivo (4). Because the main roles of protein prenylation are attachment to cellular membranes and protein-protein interactions (5, 39), it is possible that control of this modification may underlie the specificity of the function of PRL-1 in a given cell type.

It is important to note that two PRL-1 homologues, PRL-2 and PRL-3, have been identified (4, 38). PRL-2 has been cloned and has been found to be expressed in a number of tissues, with particularly high mRNA levels in skeletal muscle. PRL-3 was found in an expressed sequence tag database search for PRL-1 homologues and has not been fully cloned. Both proteins are predicted to be highly homologous to PRL-1, with little homology to other PTPases outside of the active site (24, 25, 38). Specific antibodies are not available for either of the two homologues. Because there is a significant degree of homology, it is possible that some of the results noted here could in fact reflect expression of PRL-2 or PRL-3 instead of PRL-1. However, several lines of evidence suggest that this is not the case. First, we have obtained a PRL-2 clone (generous gift of Dr. Gilbert Lenoir) and expressed it in bacteria. Our PRL-1 antibody does not cross-react with this protein on Western blots (R. Diamond, unpublished data). Second, PRL-1 mRNA expression has been identified by in situ hybridization in developing lung, kidney, and midgut tissues (29). The current work is the first to examine the expression pattern of the PRL-1 protein in these tissues. Because the in situ hybridization results, which are more specific for a particular homologue, agree with our data on PRL-1 protein expression, it is likely that our data accurately represent PRL-1 expression and not that of its cellular homologues. Third, Northern blot data do not indicate expression of PRL-3 in kidney (38), as we have shown here, whereas the Northern blot results do indicate expression of PRL-3 in heart (38), a tissue we found not to be stained by the PRL-1 antibody (data not shown). Fourth, anti-PRL-1 staining can be specifically blocked with bacterially expressed PRL-1 protein (37). Finally, we have previously documented the specificity of our anti-PRL-1 antibody with Western blot and immunofluorescence data after PRL-1 overexpression and have shown the abrogation of these staining patterns after anti-PRL-1 depletion of the antisera by affinity chromatography (6). In short, although we cannot definitively exclude that some of our data may reflect expression of PRL-1 homologues, this possibility appears unlikely.

Because PRL-1 is a tyrosine phosphatase, a complete understanding of its cellular function awaits the precise identification of its natural substrates and other interacting proteins. In this regard, we have recently identified a novel transcription factor that interacts with PRL-1 with the use of the yeast two-hybrid system (Diamond et al., unpublished observations). PRL-1 might positively or negatively regulate the DNA binding or transactivation of this transcription factor. If the primary role of PRL-1 is in transcriptional regulation, its localization to the cytoplasm under some circumstances could represent modulation of its activity by sequestration. Ultimately, experiments involving forced under- and overexpression of PRL-1 in specific cells and tissues will be necessary to investigate its role in bringing about the phenotypes with which its expression is associated. Such experiments are currently underway in intestinal cell lines in our laboratory.


    ACKNOWLEDGEMENTS

The authors thank Dr. Anil K. Rustgi for thoughtful comments and suggestions on this manuscript.


    FOOTNOTES

This work was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grant RO1-DK-52216 (R. H. Diamond) and by the Morphology Core of the University of Pennsylvania NIH/NIDDK Center for Molecular Studies in Digestive and Liver Diseases P30-DK-50306.

Address for reprint requests and other correspondence: R. H. Diamond, GI Division, Univ. of Pennsylvania School of Medicine, 664 Clinical Research Bldg., 415 Curie Blvd., Philadelphia, PA 19104-6145 (E-mail: diamondr{at}mail.med.upenn.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. §1734 solely to indicate this fact.

Received 30 November 1999; accepted in final form 12 April 2000.


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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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Am J Physiol Gastrointest Liver Physiol 279(3):G613-G621
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