Nuclear localization of beta -catenin and loss of apical brush border actin in cystic tubules of bcl-2 -/- mice

Christine M. Sorenson

George M. O'Brien Kidney and Urological Diseases Center, Renal Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, 63110


    ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References

Tight regulation of the rates of cell proliferation and apoptosis is critical for normal nephrogenesis. Nephrogenesis is profoundly affected by the loss of bcl-2 expression. Bcl-2-deficient (bcl-2 -/-) mice are born with renal hypoplasia and succumb to renal failure secondary to renal multicystic disease. Cell-cell and cell-matrix interactions impact tissue architecture by modulating cell proliferation, migration, differentiation, and apoptosis. E-cadherin mediates calcium-dependent homotypic cell-cell interactions that are stabilized by its association with catenins and the actin cytoskeleton. The contribution of altered cell-cell interactions to renal cystic disease has not been delineated. Cystic kidneys from bcl-2 -/- mice displayed nuclear localization of beta -catenin and loss of apical brush border actin staining. The protein levels of alpha -catenin, beta -catenin, actin, and E-cadherin were not altered in cystic kidneys compared with normal kidneys. Therefore, an altered distribution of beta -catenin and actin, in kidneys from bcl-2 -/- mice, may indicate improper cell-cell interactions interfering with renal maturation and contributing to renal cyst formation.

alpha -catenin; adherens junctions; actin; renal multicystic disease


    INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References

RENAL CYSTIC DISEASE (RCD) includes both autosomal dominant and recessive forms, as well as acquired forms. RCD has profound clinical implications and affects a significant number of individuals in the United States (9). Abnormalities in kidney development, growth, differentiation, and apoptosis precede and play a causative role in RCD (3, 4, 7, 8, 10, 22, 23). However, the precise manner in which abnormalities in these processes are causative of RCD is not completely understood.

Proper regulation of apoptosis is an absolute requirement for normal nephrogenesis (6, 18, 21). B-cell lymphoma/leukemia-2 (bcl-2) is a novel protooncogene that inhibits apoptosis in a variety of settings (6). Apoptosis within the developing kidney occurs in areas where bcl-2 is not expressed (5). The loss of bcl-2 expression has a profound effect on nephrogenesis. Transgenic mice that manifest a loss of function mutation for bcl-2 (bcl-2 -/- mice) complete embryonic development but are born with renal hypoplasia, which results from excessive apoptosis of the metanephric blastema during kidney formation (19). Eventually these animals succumb to renal failure secondary to RCD (19, 21). Significant cyst formation in kidneys of the bcl-2 -/- mice coincides with kidney maturation. Cyst formation occurs together with hyperproliferation of tubular epithelium and increased apoptosis relative to that observed in wild-type (bcl-2 +/+) mice (18).

Cell-cell and cell-matrix interactions impact cell proliferation, migration, differentiation, and apoptosis. Cell adhesion mechanisms determine tissue architecture and are responsible for cell assembly and connection to the internal cytoskeleton (12). Cadherins involved in homotypic interactions mediating cell-cell adhesion colocalize to sites of cell-cell contact with actin-associated junctions (12).

Cadherin-mediated cell-cell adhesion is necessary for establishment and maintenance of epithelial cell polarity and tight junctions. Several cadherins are expressed in the kidney including E-cadherin, K-cadherin, N-cadherin, and cadherin-11. The interactions of E-cadherin are well documented particularly in the kidney and in Madin-Darby canine kidney (MDCK) cells. Cell adhesions mediated by E-cadherin require intracellular attachment to the actin cytoskeleton. This is accomplished through E-cadherin's cytoplasmic interaction with catenins. E-cadherin complexes with beta -catenin through its cytoplasmic domain. Cadherin-catenin complexes are formed when alpha -catenin binds to beta -catenin. alpha -Catenin then can link these cadherin-catenin complexes to the actin cytoskeleton (12). Catenins also act as general linkers or adapters by interacting with transmembrane or cytoplasmic proteins. For example, beta -catenin associates with the adenomatous polyposis coli (APC) tumor suppressor protein, epidermal growth factor receptor, and the tight junction protein zonula occluden-1 protein (2, 11, 13). However, the contribution of these interactions during renal maturation or renal multicystic disease has not been delineated.

This study examines the expression and distribution of alpha -catenin, beta -catenin, actin, and E-cadherin, which participate in establishment and maintenance of cell-cell adhesion and actin cytoskeletal organization in postnatal kidneys from bcl-2 +/+ and bcl-2 -/- mice. Disruption of the cadherin/catenin complex organization occurred in kidneys from bcl-2 -/- mice. An altered distribution of beta -catenin and loss of brush border actin staining were observed after significant cyst formation had occurred. Therefore, the aberrant distribution of proteins that participate in cell-cell adhesion accompany and may precipitate renal cyst formation in the absence of bcl-2.


    METHODS
Top
Abstract
Introduction
Methods
Results
Discussion
References

Animal breeding. Bcl-2 heterozygote animals were interbred. The genotypes of the offspring were determined by PCR analysis. The Neo primers (5'-GCTCTTCAGCAATATCACGG-3' and 5'-GGAGAGGCTATTCGGCTATG-3' ) yielded a 650-bp fragment, and the bcl-2 primers (5'-CTTTGTGGAACTGTACGGCCCCAGCATGCG-3' and 5'-ACAGCCTGCAGCTTTGTTTCATGGTACATC-3') yielded a 215-bp fragment. Thus the wild-type animals would have only the bcl-2 fragment, the heterozygote animals would have both fragments, and the bcl-2 -/- animals would have only the Neo fragment.

Processing of kidneys for histological studies and immunohistochemistry. Kidneys were surgically removed from mice, placed in OCT compound (VWR Scientific, St. Louis, MO) and rapidly frozen. Sections of 7 µm each were placed on polylysine coated slides (Sigma, St. Louis, MO). In experiments examining the expression of E-cadherin, alpha -catenin, and beta -catenin, the sections were fixed in cold acetone, washed in PBS, and incubated in PBS blocking buffer (PBS containing 1% bovine serum albumin, 0.3% Triton X-100, and 0.2% skim milk powder) for 15 min. The sections were then incubated with rabbit polyclonal antibodies to alpha -catenin (1:500, Sigma) or beta -catenin (1:600, Sigma) or rat monoclonal antibodies to uvomorulin (1:600, Sigma) and Lotus tetragonobolus agglutinin (LTA; Vector Labs, Burlingame, CA) overnight at 4°C. The sections were stained with LTA as a marker for proximal tubules (PT) as well as the apical membrane. The sections were incubated with appropriate indocarbocyanine (CY3)-labeled secondary antibody (Jackson ImmunoResearch, West Grove, PA). Some of the sections stained with beta -catenin were incubated with Hoechst 33258 (1:1,000; Sigma) in PBS for 15 min and rinsed in PBS. In addition, for DNA synthesis studies, sequential kidney sections from mice injected with 5-bromo-2'-deoxyuridine (BrdU) were stained with anti-BrdU as previously described (18) or anti-beta -catenin and LTA. To examine actin expression, the sections were fixed in 3% paraformaldehyde on ice for 20 min, washed in PBS, incubated in PBS-blocking buffer, and incubated in PBS-blocking buffer containing tetramethylrhodamine-5-(and 6)-isothiocyanate (TRITC)-labeled phalloidin (1: 150) (Sigma) for 2 h at room temperature. The slides were then photographed.

Protein lysate preparation and Western blot analysis. Kidneys were homogenized and sonicated in a buffer containing 142.5 mM KCl, 5 mM MgCl2, 10 mM HEPES, pH 7.5, 1% Nonidet P-40, 2 mM orthovanadate, 2 mM sodium fluoride, and complete protease inhibitor cocktail (Boehringer Mannheim, Indianapolis, IN). The protein concentration was determined utilizing a Bio-Rad DC protein assay. Twenty micrograms of total protein lysate was electrophoresed in a 4-20% polyacrylamide gel and transferred to a Hybond ECL nitrocellulose membrane (Amersham, Arlington Heights, IL). The membranes were blocked in TBST (20 mM Tris, pH 7.6, 137 mM NaCl, and 0.05% Tween) containing 3% bovine serum albumin and 3% nondairy creamer for 1 h at room temperature. The membranes were then incubated with rabbit polyclonal antibodies to alpha -catenin (1:4,000; Sigma), rabbit polyclonal antibodies to beta -catenin (1:4,000; Sigma), rat monoclonal antibodies to uvomorulin (1:4,000; Sigma), or mouse monoclonal antibodies to actin (1:500; Sigma) overnight at 4°C. The membranes were then washed with TBST, incubated with the appropriate secondary antibody (Pierce, Rockford, IL), washed with TBST, and developed with ECL (Amersham).


    RESULTS
Top
Abstract
Introduction
Methods
Results
Discussion
References

Altered organization of actin in absence of bcl-2. The organization of cadherin/catenin complexes was examined in kidneys from bcl-2 +/+ and bcl-2 -/- mice to determine whether disruption of these interactions occurred during renal cyst formation. The distribution of actin was examined at birth, prior to cyst formation, and later, postnatal day 21 (P21), when significant cyst formation is noted in kidneys from bcl-2 -/- mice (18). Actin staining of kidneys from newborn (P0) bcl-2 +/+ and bcl-2 -/- mice was similar. In the nephrogenic zone (capsule noted by arrows), apical actin staining was noted in PT and condensates, whereas actin staining on the periphery of cells was noted in interstitium (Fig. 1, A and B). Kidneys from P21 bcl-2 +/+ mice displayed apical brush border actin staining in PT (Fig. 1C, arrowhead) and on the periphery of individual cells in distal tubules and collecting duct. However, the distribution of actin in kidneys from P21 bcl-2 -/- mice was altered. Cystic PT (Fig. 1D), as well as cystic distal tubules and collecting duct, displayed a loss of apical brush border actin staining (Fig. 1D, solid arrow) although some noncystic PT did retain apical brush border actin staining (open arrow, Fig. 1D). Peripheral actin staining of cells in cystic tubules was never observed. Thus the altered actin distribution observed in cystic kidneys may influence interactions of other proteins that are linked to the actin cytoskeleton.


View larger version (60K):
[in this window]
[in a new window]
 
Fig. 1.   Actin localization in kidneys from bcl-2 +/+ and bcl-2 -/- mice: fluorescence photomicrographs of histological sections of kidney from the nephrogenic zone of newborn (P0, A and B) or cortex of postnatal day 21 (P21; C and D) bcl-2 +/+ (A and C) and bcl-2 -/- mice (B and D) stained with tetramethylrhodamine-5-(and 6)-isothiocyanate (TRITC)-phalloidin. Arrowheads in A and B point to the renal capsule. Arrowhead in C indicates proximal tubules (PT) with apical brush border actin staining. Cystic proximal tubules (D) demonstrate a loss of apical brush border actin staining (solid arrowhead). Solid arrows in D indicate basal membrane. Open arrow in D indicates noncystic proximal tubule. E and F: Lotus tetragonobolus agglutinin (LTA) staining of C and D, respectively. Results are representative of 8 sets of kidneys. GM, glomeruli. Scale bar in bottom left corner is equal to 40 µm.

Altered organization and nuclear localization of beta -catenin accompanies cyst formation. Cadherin-catenin complexes attach to the actin cytoskeleton. These interactions are essential for stabilization of adherens junctions and communication from the outside of the cell to the inside. E-cadherin complexes with beta -catenin through its cytoplasmic domain (12). Thus altered expression or distribution of beta -catenin could affect adherens junction integrity. The distribution of beta -catenin was examined in kidneys from bcl-2 +/+ and bcl-2 -/- mice. beta -Catenin was expressed in all nephron segments. Kidneys from newborn bcl-2 +/+ and bcl-2 -/- mice demonstrated similar staining for beta -catenin with intense immunoreactivity on basolateral membranes and at sites of cell-cell contacts (Fig. 2, A and B). Kidneys from P21 bcl-2 +/+ mice demonstrated beta -catenin immunoreactivity at sites of cell-cell contacts (Fig. 2C). The distribution of beta -catenin within nephron segments from bcl-2 -/- mice remained similar to that of bcl-2 +/+ littermates until significant cyst formation was observed. At P21, cystic kidneys from bcl-2 -/- mice demonstrate nuclear beta -catenin staining. The arrow in Fig. 2D indicates nuclear beta -catenin staining in a collecting duct from a kidney of a P21 bcl-2 -/- mouse, which can be compared with the collecting duct in a kidney from a normal littermate (arrow, Fig. 2C). As illustrated in Fig. 3, A and B, nuclear localization was confirmed by incubating slides stained with beta -catenin with Hoechst 33258. Furthermore, nuclear localization of beta -catenin was typically observed in tubules in kidneys from bcl-2 -/- mice that were hyperproliferative. The arrow in Fig. 3C points to several nuclei that stain positively for beta -catenin. Staining of a sequential section for incorporation of BrdU demonstrates that many cells within this PT and in the same area in which nuclear beta -catenin staining was noted (arrow, Fig. 3D) were undergoing DNA synthesis. However, DNA synthesis did occur in areas where nuclear beta -catenin staining was not observed. In kidneys from normal P21 mice, rare nuclei stained positively for BrdU (data not shown), similar to our previous report (18).


View larger version (64K):
[in this window]
[in a new window]
 
Fig. 2.   beta -Catenin localization in kidneys from bcl-2 +/+ and bcl-2 -/- mice: representative fluorescence photomicrographs of the nephrogenic zone from P0 (A and B) and cortex of P21 (C and D) bcl-2 +/+ (A and C) and bcl-2 -/- mice (B and D) stained for beta -catenin. Solid arrowheads in A, B, and D indicate renal capsule. Arrows in C and D point to collecting duct, which in D has nuclear localization of beta -catenin. E and F: LTA staining of C and D, respectively. Micrographs are representative of >9 sets of kidneys. Scale bar in bottom left corner is equal to 40 µm.


View larger version (89K):
[in this window]
[in a new window]
 
Fig. 3.   Nuclear localization of beta -catenin in cystic kidneys from bcl-2 -/- mice: fluorescence photomicrographs of sections of kidney cortex from P21 bcl-2 -/- mice. The same section was stained for beta -catenin (A) and Hoechst 33258 (B). Arrowheads in A and B denote nuclei. Sequential sections of kidney cortex from P21 bcl-2 -/- mice were stained for beta -catenin (C) and BrdU (D). Proximal tubules are identified by staining with LTA. Arrowheads in C and D indicate nuclear localization. Scale bar in bottom left corner is equal to 40 µm.

Distribution of alpha -catenin. alpha -Catenin is another component of adherens junctions. It links cadherin-catenin complexes to the actin cytoskeleton and is detected at sites of cell-cell contacts (12). alpha -Catenin was expressed in all nephron segments. Strong basolateral membrane staining for alpha -catenin was observed in kidneys from P0 bcl-2 +/+ and bcl-2 -/- mice (Fig. 4, A and B). The pattern of expression and distribution of alpha -catenin was similar in kidneys from P0 and P21 bcl-2 +/+ and bcl-2 -/- mice.


View larger version (69K):
[in this window]
[in a new window]
 
Fig. 4.   Localization of alpha -catenin in kidneys from bcl-2 +/+ and bcl-2 -/- mice: fluorescence photomicrographs of sections of nephrogenic zone from P0 (A and B) and cortex from P21 (C and D) kidneys from bcl-2 +/+ (A and C) and bcl-2 -/- mice (B and D) stained for alpha -catenin. Arrowheads in A and B indicate renal capsule. E and F: LTA staining of C and D, respectively. Micrographs are representative of 8 sets of kidneys. Scale bar in bottom left corner is equal to 40 µm.

Distribution of E-cadherin. E-cadherin is involved in homotypic interactions mediating cell-cell adhesion and localizes to sites of cell-cell contacts with actin-associated junctions. Cell adhesion mediated by E-cadherin requires intracellular attachment to the actin cytoskeleton, which is accomplished through interactions with catenins (12). E-cadherin was expressed in most nephron segments, except glomeruli, in kidneys from bcl-2 +/+ and bcl-2 -/- mice. Kidneys from bcl-2 +/+ and bcl-2 -/- mice demonstrated a similar pattern of expression and distribution at P0 and P21 (Fig. 5).


View larger version (47K):
[in this window]
[in a new window]
 
Fig. 5.   Localization of E-cadherin in kidneys from bcl-2 +/+ and bcl-2 -/- mice: fluorescence photomicrographs of kidney sections from the nephrogenic zone of P0 (A and B) and cortex of P21 (C and D) bcl-2 +/+ (A and C) and bcl-2 -/- mice (B and D) stained for E-cadherin. Solid arrowheads in A and B indicate the location of the renal capsule. Open arrow in B indicates E-cadherin staining of an LTA-positive proximal tubule. Solid arrow in D illustrates a noncystic proximal tubule, whereas the open arrow points to apical surface of a cystic proximal tubule. E and F: LTA staining of C and D, respectively. Micrographs are representative of 8 sets of kidneys. Scale bar in bottom left corner is equal to 40 µm.

Levels of adherens junction proteins were not altered during cyst formation. Western blot analysis was utilized to determine the levels of alpha -catenin, beta -catenin, actin, and E-cadherin in kidney lysates. Protein lysates were prepared from kidneys of P7 and P21 bcl-2 +/+ and bcl-2 -/- mice. Examination of protein levels at P7 determined levels prior to kidney maturation and prior to significant renal cyst formation (bcl-2 -/-), whereas examination at P21 determined levels following kidney maturation and after significant renal cyst formation was observed (bcl-2 -/-). Illustrated in Fig. 6 is a representative Western blot. The level of alpha -catenin, beta -catenin, actin, and E-cadherin was unchanged between comparable kidney protein lysates from bcl-2 +/+ and bcl-2 -/- mice at P7 or P21 (Fig. 6). Although the level of actin did increase in lysates from mature bcl-2 +/+ and bcl-2 -/- kidneys, it occurred to a similar extent (Fig. 6).


View larger version (53K):
[in this window]
[in a new window]
 
Fig. 6.   Level of protein expression. Western blot analysis was performed with protein lysates prepared from P0 and P21 bcl-2 +/+ and bcl-2 -/- kidneys. Protein lysates (20 µg) were analyzed by SDS-PAGE and transferred to a nitrocellulose membrane. Membranes were incubated with antibodies to alpha -catenin, beta -catenin, E-cadherin, or actin as indicated. Western blot analysis was repeated 3 times using different kidney lysates with the indicated results.


    DISCUSSION
Top
Abstract
Introduction
Methods
Results
Discussion
References

Bcl-2 -/- mice are born with oligomeganephronic hypoplasia and succumb to renal failure secondary to multicystic renal disease (19, 21). Pronounced renal cyst formation in bcl-2 -/- mice is noted when renal maturation should be completed (18). The expression of alpha -catenin, beta -catenin, actin, and E-cadherin was examined to determine whether altered expression and/or organization occurred during renal cyst formation. The distribution of actin and beta -catenin was altered when significant cyst formation was noted following renal maturation in the bcl-2 -/- mice. Piepenhagen and Nelson (14) have observed that alpha -catenin and beta -catenin are ubiquitously expressed along the nephron, similar to the distribution of E-cadherin. However, E-cadherin, unlike alpha -catenin and beta -catenin, is not expressed in glomeruli or the initial proximal tubular segment (14, 15). The studies presented here demonstrated expression in the same nephron segments, both in kidneys from normal and bcl-2 -/- mice, as observed by Piepenhagen and co-workers (14, 15). In contrast, the distribution of actin and beta -catenin was altered within nephron segments of kidneys from bcl-2 -/- mice.

The pathways underlying cyst formation remain a mystery. Numerous abnormalities including altered proliferative and apoptotic capacities, epithelial membrane polarity, and extracellular matrix and fluid secretion have been identified (1, 3, 10, 17, 23). Investigators have drawn parallels between a renal cystic phenotype and a benign tumor or epithelial cells that never fully differentiate (9). In both cases, RCD is compared with states that are proliferative and motile. Perhaps in kidneys from the bcl-2 -/- mice, adherens junctions do not form properly, disrupting renal maturation and resulting in renal multicystic disease.

The positioning of cells into organs during morphogenesis relies on proper regulation of cell-cell interactions and formation of adherens junctions. Cadherin/catenin complexes play a central role in these interactions. In the kidney, E-cadherin-mediated contacts may generate a basal level of cell-cell adhesion with additional strength to cell-cell contacts in the distal nephron being provided by desmosomal junctions (15). In addition, studies with MDCK cells demonstrate an essential role for dynamic beta -catenin-APC protein interactions in the regulation of cell migration during epithelial tubulogenesis (16). Thus disruption of the E-cadherin/catenin complex could have a profound effect on kidney development or renal maturation.

Cystic kidneys from bcl-2 -/- mice display nuclear beta -catenin staining, loss of apical brush border actin staining, but normal alpha -catenin staining. In humans, adenomatous polyps demonstrate nuclear beta -catenin staining with a concomitant downregulation of membrane staining as well a reduced expression of E-cadherin. However, alpha -catenin staining was not altered in these polyps (20). These alterations are very similar to those observed during renal cyst formation in the bcl-2 -/- mice.

beta -Catenin functions in signal transduction initiated by wingless/Wnt and is localized to the nucleus upon activation of this pathway (2, 11). beta -Catenin binds to the transcription factors Tcf and Lef-1 and tumor suppressor APC (2, 11). The binding to the latter may impact migration and tubulogenesis (16). Thus it is consistent that nuclear localization of beta -catenin in cystic tubules correlates with an increased proliferative capacity of cells within these tubules. Therefore, an altered distribution of these proteins may lead to disruption of cadherin/catenin complexes and cell-cell adhesion and precipitate renal cyst formation. However, whether these changes are the direct or indirect result of the loss of bcl-2 requires further investigation.


    ACKNOWLEDGEMENTS

I thank Dr. Adrianna Dusso and Dr. Marc Hammerman for critical reading of the manuscript, Dr. Nader Sheibani for insightful discussions, and Dr. Kevin Ho for computer graphic expertise.


    FOOTNOTES

This research was funded by the Polycystic Kidney Research Foundation. I am funded by a Scientist Development Grant from the American Heart Association.

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.

Address for reprint requests: C. M. Sorenson, Renal Division Box 8126, Washington Univ. School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110.

Received 21 July 1998; accepted in final form 22 October 1998.


    REFERENCES
Top
Abstract
Introduction
Methods
Results
Discussion
References

1.   Avner, E. Epithelial polarity and differentiation in polycystic kidney disease. J. Cell Sci. 17: 217-222, 1993.

2.   Barth, A. I. M., I. S. Nathke, and W. J. Nelson. Cadherins, catenins and APC protein: interplay between cytoskeletal complexes and signaling pathways. Curr. Opin. Cell Biol. 9: 683-690, 1997[Medline].

3.   Calvet, J. P. Polycystic kidney disease: primary extracellular matrix abnormality or defective cellular differentiation? Kidney Int. 43: 101-108, 1993[Medline].

4.   Carone, F. A., R. Bacallo, and Y. S. Kanwar. Biology of disease: biology of polycystic kidney disease. Lab. Invest. 70: 437-448, 1994[Medline].

5.   Chandler, D., A. K. El-Naggar, S. Brisbay, R. W. Redline, and T. J. McDonnell. Apoptosis and expression of the bcl-2 proto-oncogene in the fetal and adult human kidney: evidence for the contribution of bcl-2 expression to renal carcinogenesis. Hum. Pathol. 25: 789-796, 1994[Medline].

6.   Farrow, S. N., and R. Brown. New members of the bcl-2 family and their protein partners. Curr. Opin. Genet. Dev. 6: 45-49, 1996[Medline].

7.   Fick, G. M., and P. Gabow. Hereditary and acquired cystic disease of the kidney. Kidney Int. 46: 951-964, 1994[Medline].

8.   Gabow, P. Polycystic kidney disease: clues to pathogenesis. Kidney Int. 40: 989-996, 1991[Medline].

9.   Grantham, J. J. Polycystic kidney disease: neoplasia in disguise. Am. J. Kidney Dis. 15: 110-116, 1990[Medline].

10.   Grantham, J. J. Fluid secretion, cellular proliferation, and the pathogenesis of renal epithelial cysts. J. Am. Soc. Nephrol. 3: 1843-1857, 1993.

11.   Gumbiner, B. M. Carcinogenesis: a balance between beta -catenin and APC. Curr. Biol. 7: R443-R446, 1997[Medline].

12.   Hinck, L., I. S. Nathke, J. Papkoff, and W. J. Nelson. beta -Catenin: a common target for the regulation of cell adhesion by Wnt-1 and Src signaling pathways. Trends Biochem. Sci. 19: 538-542, 1994[Medline].

13.   Huber, O., C. Bierkamp, and R. Kemler. Cadherins and catenins in development. Curr. Opin. Cell Biol. 8: 685-691, 1996[Medline].

14.   Piepenhagen, P. A., and W. J. Nelson. Differential expression of cell-cell and cell-substratum adhesion proteins along the kidney nephron. Am. J. Physiol. 269 (Cell Physiol. 38): C1443-C1449, 1995.

15.   Piepenhagen, P. A., L. L. Peters, S. E. Lux, and W. J. Nelson. Differential expression of Na+-K+-ATPase, ankyrin, fodrin and E-cadherin along the kidney nephron. Am. J. Physiol. 269 (Cell Physiol. 38): C1417-C1432, 1995[Abstract/Free Full Text].

16.   Pollack, A. L., A. I. M. Barth, Y. Altschuler, W. J. Nelson, and K. E. Mostov. Dynamics of beta -catenin interactions with APC protein regulate epithelial tubulogenesis. J. Cell Biol. 137: 1651-1662, 1997[Abstract/Free Full Text].

17.   Sorenson, C. Life, death and kidneys: regulation of renal programmed cell death. Curr. Opin. Nephrol. Hypertens. 7: 5-12, 1998[Medline].

18.   Sorenson, C. M., B. J. Padanilam, and M. R. Hammerman. Abnormal postpartum renal development and cystogenesis in the bcl-2 -/- mouse. Am. J. Physiol. 271 (Renal Fluid Electrolyte Physiol. 40): F184-F193, 1996[Abstract/Free Full Text].

19.   Sorenson, C. M., S. A. Rogers, S. J. Korsmeyer, and M. R. Hammerman. Fulminant metanephric apoptosis and abnormal kidney development in bcl-2-deficient mice. Am. J. Physiol. 268 (Renal Fluid Electrolyte Physiol. 37): F73-F81, 1995[Abstract/Free Full Text].

20.   Valizadeh, A., A. J. Karayiannakis, I. El-Hariry, W. Kmiot, and M. Pignatelli. Expression of E-cadherin-associated molecules (alpha -, beta -, and gamma -catenins and p120) in colorectal polyps. Am. J. Pathol. 150: 1977-1984, 1997[Abstract].

21.   Veis, D. J., C. M. Sorenson, J. R. Shutter, and S. J. Korsmeyer. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys and hypopigmented hair. Cell 76: 777-779, 1994[Medline].

22.   Welling, L. W., and J. J. Grantham. Cystic and developmental diseases of the kidney. In: The Kidney, edited by B. M. Brenner, and F. C. Rector. Philadelphia, PA: Sanders, 1991.

23.   Wilson, P. D., and A. C. Sherwood. Tubulocystic epithelium. Kidney Int. 39: 450-463, 1991[Medline].


Am J Physiol Renal Physiol 276(2):F210-F217
0002-9513/99 $5.00 Copyright © 1999 the American Physiological Society