| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
-catenin compensates for the loss of 
-catenin in adult cardiomyocytes
1Cardiovascular Research Institute, South Dakota Health Research Foundation, 2Department of Laboratory Medicine and Pathology, University of South Dakota Sanford School of Medicine and Sioux Valley Hospitals and Health System, Sioux Falls, South Dakota; and 3Department of Pathology, Zhongshan University, Fifth Affiliated Hospital, Zhuhai, Guangdong Province, People’s Republic of China
Submitted 2 June 2006 ; accepted in final form 23 August 2006
 |
ABSTRACT |
|---|
 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
-catenin signaling controls embryonic development, tumorigenesis, cell shape, and polarity. The role of this pathway in myocyte shape regulation during cardiac hypertrophy and failure is, however, not clearly defined. Since homozygous knockout of -catenin is embryonically lethal, we have deleted -catenin genes specifically in the heart of adult mice by crossing loxP-flanked -catenin mice with transgenic mice expressing tamoxifen-activated MerCreMer protein (MCM) driven by the 
-myosin heavy chain promoter. Administration of tamoxifen to homozygous loxP-flanked -catenin mice positive for MCM induces the deletion of -catenin only in cardiomyocytes. Immunolabeling with -catenin antibody demonstrates that 90% of cardiomyocytes completely lose their -catenin expression but maintain normal rod-shaped morphology. The intercalated disk of cardiomyocytes lacking -catenin is morphologically unremarkable with normal distribution of vinculin, N-cadherin, desmoplakin, ZO-1, connexin43, and -, 
-, and p120 catenins. The expression level of these proteins, except that of -catenin, is also similar in tamoxifen-treated and control mice with both homozygous loxP-flanked -catenin genes and the MCM transgene. Western blot analyses reveal that -catenin increases in the heart of -catenin knockout mice compared with controls. Confocal microscopy also demonstrates that -catenin has significantly increased in the intercalated disk of cardiomyocytes lacking -catenin. Echocardiographic data indicate that the knockout mice maintain normal ventricular geometry and cardiac function. The results suggest that upregulation of -catenin can compensate for the loss of -catenin in cardiomyocytes to maintain normal cardiac structure and function.
catenin; heart; intercalated disk; cardiomyocyte; knockout
-catenin, which in turn links to actin cytoskeleton via -catenin (23). This traditional view of adherens junctions, however, has recently been challenged (32). New evidence has demonstrated that -catenin regulates actin dynamics rather than stably associating with actin (7). Molecular genetic studies have shown that N-cadherin plays a critical role in myocyte differentiation and sarcomerogenesis during heart development (25, 29). N-cadherin-based adherens junctions initiate the formation and maintain the structural integrity of the intercalated disk. Defects in adherens junctions have severe effects on both desmosomes and gap junctions. Deletion of N-cadherin leads to a cell adhesion defect in mesodermal and endodermal cell layers of the yolk sac. Cardiomyocytes disassociate in the primitive heart without the formation of a heart tube (25). Cardiac-specific deletion of N-cadherin in adults causes extensive remodeling of the intercalated disk, leading to perturbation of connexin function, conduction abnormality, and arrhythmogenesis (18, 20).
-Catenin is the key molecule linking cadherins to the actin cytoskeleton and only targets to adherens junctions. As a close relative of -catenin, -catenin is present in both adherens junctions and desmosomes. Complete knockout of -catenin is embryonically lethal due to a severe cardiac defect (2). In -catenin-deleted mice, -catenin becomes localized to desmosomes and associates with desmoglein (3). This substitution, however, cannot fully compensate for the absence of -catenin, and desmosomes are structurally altered and reduced significantly in number (2). The deletion of -catenin is also embryonically lethal and affects anterior-posterior axis formation (13). Endothelium-specific inactivation of -catenin alters vascular patterning without apparent effects on early phases of vasculogenesis and angiogenesis (5). The deletion of -catenin in endothelial cells also affects cardiac septation, and the mice die between embryonic days 11.5 and 13.0 (22). The functional and structural consequence of -catenin deletion in cardiomyocytes, however, remains to be investigated.
To determine the role of -catenin in the heart, the -catenin gene was specifically deleted in cardiomyocytes of adult mice by crossing loxP-flanked -catenin mice (4) with transgenic mice expressing a tamoxifen-activated MerCreMer protein (MCM) under the control of the -myosin heavy chain promoter (28). Surprisingly, the cardiomyocyte-restricted -catenin knockout mice displayed normal ventricular geometry and function. The expression and distribution of vinculin, N-cadherin, desmoplakin, ZO-1, connexin43, -catenin, and p120 catenins also were maintained. The expression level of -catenin, however, was significantly increased in the -catenin knockout mice compared with control mice without tamoxifen injection. Confocal microscopy further confirmed that -catenin was significantly increased in the intercalated disk of cardiomyocytes lacking -catenin. These findings suggest that the upregulation of -catenin in -catenin knockout adult mice can compensate for the absence of -catenin to maintain normal cardiac structure and function.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
-catenin gene were originally generated in Dr. R. Kemler’s laboratory (4) and obtained from The Jackson Laboratory (Bar Harbor, ME). Transgenic mice overexpressing Cre recombinase protein fused to two mutant estrogen receptor ligand-binding domains under the control of the -myosin heavy chain promoter (MCM) were created in Dr. J. D. Molkentin’s laboratory (University of Cincinnati) (28) and are now available through The Jackson Laboratory. Homozygous mice with the floxed -catenin alleles were crossed with MCM mice. Heterozygous floxed -catenin mice positive for MCM were backcrossed with homozygous floxed -catenin mice. A pilot study was conducted to investigate the efficiency and specificity of tamoxifen-induced deletion of -catenin in the hearts of 3- to 4-mo-old mice. Six heterozygous and homozygous floxed -catenin mice and wild-type mice positive for MCM were intraperitoneally injected with tamoxifen in peanut oil or just peanut oil without tamoxifen (28). Four weeks after injection, DNA isolated from atrial and ventricular tissue was subjected to PCR amplification.
A total of twenty 3- to 4-mo-old homozygous floxed -catenin mice positive for MCM were randomly divided to two equal groups injected intraperitoneally with or without tamoxifen. Echocardiography was performed 4 wk after injection, and animals were killed for tissue collection. Six animals from each group were randomly assigned for myocyte isolation, two for collection of atrial and ventricular tissues, and two for histological examination. Different organs and atrial tissue were also collected for PCR amplification to determine the organ specificity of -catenin deletion after tamoxifen injection. All procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animals (US Department of Health and Human Services, NIH Publication 85-23) and were approved by the University of South Dakota Animal Care and Use Committee.
Genotyping.
To identify loxP floxed -catenin alleles, we isolated DNA from tail or toe biopsy of neonates or ear punch of adults following proteinase K digestion as described previously (4). For -catenin genes, a two-primer set amplifies a 324-bp band representing the loxP floxed -catenin allele and a 221-bp product displaying wild-type allele, respectively. To detect deleted -catenin allele after tamoxifen injection, we added a third primer generating a 500-bp band of recombined -catenin allele in addition to the 324- and 221-bp products (4). For MCM transgene (28), sense primer (GTC TGA CTA GGT GTC CTT CT) and antisense primer (CGT CCT CCT GCT GGT ATA G) were used to generate a 410-bp product. Primers for the desmin gene were added as internal control in the same reaction.
Echocardiography. Four weeks after the injection, transthoracic echocardiography was performed using a high-resolution Vevo600 echocardiogram system with a 30-MHz transducer (Visual Sonics, Toronto, Canada). The animals were anesthetized using a minimum dose of isoflurane (1–2%) via a nose cone throughout the procedure. Two-dimensional parasternal short- and long-axis images of the left ventricle were acquired at midventricle between the papillary muscles with guided M-mode recordings. Measurements of diastolic and systolic wall thicknesses and left ventricular end-diastolic and end-systolic chamber dimensions were made from leading edge to leading edge of the tracings. Ejection fraction (EF) and percent fractional shortening (FS) were calculated with the accompanying software.
Antibodies.
Rabbit polyclonal antibodies against - and -catenins and mouse monoclonal antibodies for pan-cadherin, vinculin, and -catenin were obtained from Sigma-Aldrich (St. Louis, MO). Mouse monoclonal antibodies against connexin43 and ZO-1 were purchased from Zymed Laboratories (San Francisco, CA). Mouse monoclonal antibodies against N-cadherin, -catenin, and p120 catenin were acquired from BD Transduction Laboratories (Lexington, KY). Rabbit polyclonal anti-desmoplakin antibody was ordered from Serotec (Raleigh, NC). Secondary goat anti-rabbit IgG or anti-mouse IgG antibodies conjugated with Alexa Fluor 488 or 568 (Molecular Probes, Eugene, OR) were used for immunofluorescent labeling. Horseradish peroxidase-linked donkey anti-rabbit IgG antibody and goat anti-mouse IgG antibody for Western blots were obtained from Santa Cruz Biotechnology (Santa Cruz, CA).
Myocyte isolation, immunofluorescent labeling, and confocal microscopy. Hearts were perfused with 0.1% collagenase via the aorta for 8–10 min as described previously (33). After the perfusion, the ventricles were dissected free and minced in calcium-free Joklik’s medium. Isolated cardiomyocytes were filtered through a nylon mesh (250 µm). Half of the cardiomyocytes were fixed in 4% paraformaldehyde for 10 min and subsequently suspended in PBS for immunolabeling; the other half were frozen for Western blot analyses.
An aliquot of isolated cardiomyocytes was attached onto positively charged slides (33, 34). The attached cardiomyocytes were incubated with 0.5% Triton X-100 for 30 min at room temperature to permeate the plasma membrane (19). After the cardiomyocytes were washed with PBS and blocked with 1% bovine serum albumin to reduce nonspecific binding, a primary antibody was added for overnight incubation at 4°C. The primary antibody was then removed and washed with PBS. A secondary fluorochrome-conjugated antibody was incubated for 1 h at room temperature. For double labeling, a second set of antibodies was repeated for incubation. The slides were mounted in glycerol and sealed with nail polish for observation using an Olympus Fluoview 300 confocal laser scanning microscope system (Olympus America, Melville, NY). Negative controls were performed under the same conditions with the omission of the primary antibody or the use of nonspecific mouse or rabbit serum. In preliminary studies, the staining pattern of intercalated disk proteins between frozen section and isolated cardiomyocytes were compared in wild-type and -catenin knockout mice. The distribution pattern of these proteins was not altered by the isolation procedure.
Protein separation and Western blot analyses. Isolated cardiomyocytes were resuspended in 250 µl of ice-cold Tris-Triton extraction buffer (10 mM Tris·HCl, 50 mM NaCl, 5 mM EGTA, and 1% Triton X-100, pH 7.4) containing phosphatase inhibitors (0.1 mM Na3VO4, 30 mM Na4P2O7, and 50 mM NaF) and proteinase inhibitors (10 mg/ml PMSF and 1 µg/ml aprotinin). After homogenization with a Sonic Dismembrator F60 (Fisher Scientific, Pittsburgh, PA), the homogenates were centrifuged at 15,000 g for 15 min and separated into Triton-soluble supernatant and insoluble pellet. The supernatant was quantified with the bicinchoninic acid protein assay (BCA; Pierce, Rockford, IL). Equal amount of proteins were separated by Laemmli SDS-PAGE and subsequently transferred to nitrocellulose membrane. Western blots were detected with enhanced chemiluminescence detection reagents (ECL; Amersham Bioscience, Piscataway, NJ), and a VersaDoc imaging system (model 3000; Bio-Rad, Hercules, CA) was used to digitize Western blot images. The density of protein bands with each antibody was quantified with NIH Image software. The same-lane actin level was used as an internal control to ensure equal loading (34). The pellet was suspended, vortexed, and then boiled in 250 µl of Laemmli SDS sample buffer for 5 min. The same volume of the pellet as its corresponding supernatant was subjected to SDS-PAGE, and no significant amount of proteins investigated was detected in the Triton-insoluble pellet of isolated cardiomyocytes.
Statistics. Data are expressed as means (SD). A two-sample t-test was performed to determine statistical significance. A P value <0.05 was regarded as statistically significant.
|
RESULTS |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
-catenin.
To investigate tamoxifen-induced deletion of -catenin in the heart, loxP floxed--catenin heterozygous or homozygous mice and wild-type -catenin mice positive for MCM were intraperitoneally injected with tamoxifen or vehicle control. Four weeks after injection, DNA isolated from atrial and ventricular tissue was subjected to PCR genotyping with three primers (4). With these primers, three bands were amplified, a 221-bp band representing wild-type -catenin gene, a 324-bp band representing loxP flanked -catenin gene, and a 500-bp band representing recombined loxP flanked -catenin gene. The recombination occurred in both atria and ventricles of homozygous (–/–) and heterozygous (+/–) loxP flanked -catenin mice after administration of tamoxifen but not in wild-type (+/+) -catenin mice or loxP flanked -catenin mice without tamoxifen exposure (Fig. 1A). To examine tissue specificity of tamoxifen-induced -catenin recombination, we amplified DNA isolated from different organs of homozygous loxP flanked -catenin mice bearing MCM transgene with three primers by PCR. The result confirmed that the recombination occurred only in the heart (Fig. 2).
|
|
-catenin, since the majority of cells in the heart are numerically cell types other than cardiomyocytes. Four weeks after tamoxifen injection, -catenin was not detected in homozygous loxP flanked -catenin mice containing MCM by Western blots in isolated cardiomyocytes (Fig. 1B). Immunolabeling and confocal microscopy revealed that 
90% of isolated cardiomyocytes contained no -catenin in the intercalated disk after tamoxifen injection (100 cardiomyocytes counted per sample, Supplemental Fig. 1).1 Cardiomyocytes without -catenin maintained normal rod-shaped morphology. The distribution of cadherin was identical between tamoxifen-injected and control groups (Fig. 1, C–H).
Ventricular geometry and cardiac function.
Echocardiography (Table 1) performed 4 wk after tamoxifen injection revealed that there was no difference in ventricular geometry and cardiac function between homozygous loxP flanked -catenin mice with or without tamoxifen treatment. In addition, no difference was observed in heart weight or heart weight-to-body weight ratio (Table 1) 4 wk after tamoxifen injection. The hearts from -catenin knockout and wild-type mice also were histologically identical (not shown).
|
-catenin in -catenin knockout mice.
In normal cardiomyocytes, -catenin is able to target to both adherens junctions and desmosomes. Knockout of -catenin had no effect on the distribution of -catenin. Confocal microscopy demonstrated that -catenin was concentrated in the intercalated disk in both -catenin intact and deleted mice (Fig. 3, A–F). Significant increase of -catenin in the intercalated disk was observed in cardiomyocytes from -catenin knockout mice (Fig. 3A) compared with controls (Fig. 3D). Western blots with isolated cardiomyocytes also confirmed that -catenin increased significantly in the heart of -catenin deleted mice (Fig. 3G and Table 2).
|
|
-catenin has no apparent effect on adherens junctions.
-Catenin plays an important role in coupling cadherins-mediated adherens junctions to the actin cytoskeleton. To investigate the effect of -catenin deletion on adherens junctions, we examined the abundance and distribution of critical components in adherens junctions. The expression levels of N-cadherin, -catenin, and p120 catenin were similar in tamoxifen-treated and control mice with homozygous loxP-flanked -catenin and positive for MCM (Table 2 and Fig. 1B; see also Supplemental Fig. 2, A and D). Similarly, the intensity and distribution of these proteins were identical in cardiomyocytes of mice with deleted and intact -catenin genes under confocal microscopy (Fig. 1, E and F; see also Supplemental Fig. 2, B, C, E, and F).
Abundance and distribution of gap junction protein connexin43 was not changed after deletion of -catenin.
The major form of connexins in the heart is connexin 43. No change in the expression of connexin 43 was detected by Western blots in -catenin knockout mice (Table 2 and Supplemental Fig. 3G). At the same time, its localization and abundance in the intercalated disk remained unchanged in the absence of -catenin (Supplemental Fig. 3, A–F).
No change in expression and localization of desmosomal protein desmoplakin in -catenin knockout hearts.
Desmoplakin is a major component of desmosomes. It connects desmosomal cadherins to desmin filaments. Similar content of desmoplakin was present in intact or deleted -catenin mice (Table 2 and Supplemental Fig. 4A). In the absence of -catenin, desmoplakin was still targeted to the intercalated disk without any change in abundance or distributional pattern (Supplemental Fig. 4, B and C).
Localization and expression of junctional proteins vinculin and ZO-1.
Vinculin is a structural protein that associates with both the intercalated disk and cell-extracellular matrix adhesion. ZO-1, on the other hand, mainly targets to gap junctions and adherens junctions through its association with connexin 43 and N-cadherin, respectively (1). The expression levels of vinculin and ZO-1 were similar in -catenin knockout mice to that in -catenin intact animals (Table 2 and Supplemental Fig. 4, D and G). Vinculin had a circumferential distribution along the plasma membrane (Supplemental Fig. 4, E and F), whereas ZO-1 was more concentrated in the intercalated disk (Supplemental Fig. 4, H and I). The distribution and localization of vinculin and ZO-1 remained unchanged in -catenin deleted mice.
|
DISCUSSION |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
-Catenin, the mammalian homolog of Drosophila armadillo, not only plays an important role in cell-cell adhesion but also is the major component of the Wnt/wingless signal transduction pathway involved in segmental polarity and pattern formation during development (24). Inhibition of Wnt/wingless signaling is required for early cardiogenesis. Endodermal specific deletion of -catenin leads to the formation of multiple hearts (21), but -catenin signaling is required for the septation of cardiac chambers (15). Conditional inactivation of -catenin in endothelial cells prevents endothelial-mesenchymal transformation during cardiac cushion development (22). To overcome the embryonic lethality of -catenin deletion and explore its function in the heart, we deleted -catenin genes specifically in the hearts of adult mice. To our surprise, the absence of -catenin in adult mice had no apparent effect on cardiac morphology and function.
Although global deletion of -catenin is lethal and affects anterior-posterior axis formation, adherens junctions are maintained in mouse embryos without -catenin (13). In these mutant embryos, -catenin is increased in adherens junctions compensating for the absence of -catenin. Our data confirm that -catenin is upregulated in adult cardiomyocytes with -catenin deletion. Even though the heart endures higher mechanical stress than any other organ, -catenin can completely compensate for the absence of -catenin and maintains the normal structure and function of the intercalated disk in the adult heart. An alternative explanation is that -catenin is dispensable in adult hearts during physiological conditions. The consequence of -catenin deletion in the heart during embryonic development and postnatal growth, however, remains to be determined.
Normally, -catenin only targets to adherens junctions. However, -catenin is able to target to desmosomes and associate with desmoglein in the absence of -catenin (3). The relocation of -catenin to desmosomes, however, cannot fully compensate for the loss of -catenin. In -catenin knockout mice, desmosomes are significantly reduced with abnormal morphology (2). Mutation of -catenin in humans causes arrhythmogenic right ventricular cardiomyopathy. The localization and abundance of N-cadherin, - and -catenins, plakophilin-2, desmoplakin-1, and desmocollin-2 at the intercalated disk are not affected by -catenin mutation (17). Connexin43, however, is significantly diminished in cardiomyopathic hearts with -catenin mutation.
Disruption of cell-cell adhesion and a significant reduction of N-cadherin in the intercalated disk have been reported in the hearts of hereditary cardiomyopathic hamsters (8). In guinea pigs with aortic constriction, neither abundance nor organization of N-cadherin is altered in left ventricular myocytes during compensated hypertrophy and congestive heart failure (30). The normal distribution of -catenin at the intercalated disk sites is largely lost in many failing left ventricular myocytes and relocated away from the ends of myocytes. The major gap junction protein, connexin43, is often downregulated during cardiac hypertrophy and heart failure (10, 26, 30).
Genetic and mutational studies have shown that adherens junctions initiate and maintain the formation of the intercalated disk. Deletion or mutation of components of adherens junctions has dramatic effects on desmosomes and gap junctions (20, 25). On the other hand, normal structure of adherens junctions is maintained when components of desmosomes or gap junctions are deleted. Severe deficiency of desmosomes in desmoplakin deleted mice shows no apparent changes in size and numbers of adherens junctions and gap junctions (9). Mutation of desmoplakin in Carvajal syndrome significantly reduces gap junctions without major influence in adherens junctions (16). Plakophilin 2, another desmosomal protein, is the only isoform of plakophilins expressed in the heart. The deletion of plakophilin 2 in mice causes a severe defect of desmosomes in the heart (11). Again, adherens junctions are morphologically normal in the heart without plakophilin 2. Interestingly, mutation of desmin, a muscle-specific intermediate filament connected to desmosomes, causes cardiomyopathy (31) and significant changes of all three types of cell adhesions in the intercalated disk (10). Knockout of connexin43, a constituent of gap junctions, disrupts the electrical coupling between cardiomyocytes but has no apparent effects on either adherens junctions or desmosomes (12).
In addition to its role in cell-cell adhesion, -catenin also has a significant signaling function. During early development, -catenin controls axis formation and cell fate determination (24). In epithelial cells, -catenin regulates cytoskeletal organization, cell shape, and polarity (23, 24). Recent studies have demonstrated that activation of -catenin signaling is also involved in cardiac hypertrophy during pressure overload (14). High sequence homology of -catenin to -catenin suggests that they may share certain common functions (23, 24). The translocation of -catenin to the nucleus further indicates that it can function as a signaling molecule in the Wnt/wingless pathway (23, 24, 27). The function of -catenin in the nucleus, however, is not identical to that of -catenin (27). A recent study has shown that the deletion of -catenin in the heart attenuates the hypertrophic response to transaortic constriction (6). Thus the signaling role of -catenin in cardiac hypertrophy is significant in adult hearts.
|
GRANTS |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
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.
* J. Zhou, J. Qu, and X. P. Yi contributed equally to this work. 
1 The online version of this article contains supplemental data.
|
REFERENCES |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
-catenin in the skin of plakoglobin null-mutant mice. Development 126: 371–381, 1999.[Abstract]-catenin gene by Wnt1-Cre-mediated deletion results in dramatic brain malformation and failure of craniofacial development. Development 128: 1253–1264, 2001.[Abstract]-catenin gene in endothelial cells causes a defective vascular pattern and increased vascular fragility. J Cell Biol 162: 1111–1122, 2003.-catenin/T-cell factor/lymphocyte enhancer factor signaling pathway is required for normal and stress-induced cardiac hypertrophy. Mol Cell Biol 26: 4462–4473, 2006.-Catenin is a molecular switch that binds E-cadherin--catenin and regulates actin-filament assembly. Cell 123: 903–915, 2005.[CrossRef][ISI][Medline]-catenin affects mouse development at gastrulation. Development 121: 3529–3537, 1995.[Abstract]-catenin by a Wnt-independent mechanism regulates cardiomyocyte growth. Proc Natl Acad Sci USA 100: 4610–4615, 2003.-catenin pathway regulates cardiac valve formation. Nature 425: 633–637, 2003.[CrossRef][Medline]-catenin in the embryonic endoderm. Dev Cell 3: 171–181, 2002.[CrossRef][ISI][Medline]-Catenin is required for endothelial-mesenchymal transformation during heart cushion development in the mouse. J Cell Biol 166: 359–367, 2004.-catenin and specification of cell fate during embryogenesis. Genes Dev 10: 2527–2539, 1996.-catenin and plakoglobin. J Cell Biol 141: 1433–1448, 1998.This article has been cited by other articles:
|
|
 |
|
  T. Grigoryan, P. Wend, A. Klaus, and W. Birchmeier Deciphering the function of canonical Wnt signals in development and disease: conditional loss- and gain-of-function mutations of {beta}-catenin in mice Genes & Dev., September 1, 2008; 22(17): 2308 - 2341. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. E. Zemljic-Harpf, J. C. Miller, S. A. Henderson, A. T. Wright, A. M. Manso, L. Elsherif, N. D. Dalton, A. K. Thor, G. A. Perkins, A. D. McCulloch, et al. Cardiac-Myocyte-Specific Excision of the Vinculin Gene Disrupts Cellular Junctions, Causing Sudden Death or Dilated Cardiomyopathy Mol. Cell. Biol., November 1, 2007; 27(21): 7522 - 7537. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Baurand, L. Zelarayan, R. Betney, C. Gehrke, S. Dunger, C. Noack, A. Busjahn, J. Huelsken, M. M. Taketo, W. Birchmeier, et al. {beta}-Catenin Downregulation Is Required for Adaptive Cardiac Remodeling Circ. Res., May 11, 2007; 100(9): 1353 - 1362. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
