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PubMed1995

Channel inhibition by alkanols occurs at a binding site on the nicotinic acetylcholine receptor.

The mechanism by which normal alkanols longer than ethanol inhibit cation flux through the transient open state of the nicotinic acetylcholine receptor (nAcChoR) is unknown. They might act nonspecifically either by perturbing the lipid bilayer or by binding to many low affinity sites. Alternatively, they might act in a mutually exclusive manner at a well defined site on the protein. To address this problem, a rapid assay of agonist-induced 86Rb+ efflux from nAcChoR-rich Torpedo membrane vesicles was used that enabled the anesthetic-induced inhibition to be measured on a millisecond time scale, under conditions where the concentration of all ligands was raised in < 1 msec, thereby avoiding complications due to desensitization. By measuring the inhibition constant of one agent as a function of the fixed concentration of a second agent, it is possible to distinguish between nonspecific action and mutually exclusive action. Our data are inconsistent with the hypothesis that 1-octanol and 1-heptanol act in a nonspecific manner, but they are consistent with the hypothesis that these two alkanols act in a mutually exclusive manner at a well defined site. The data suggest that the alkanols sterically compete for the site, but experimental limitations prevented a less plausible model, in which there is a strong negative allosteric interaction between separate octanol and heptanol sites, from being ruled out. Should the latter interaction occur, the data indicate that occupation of one alkanol site would decrease the affinity of the other by about 50-fold. The local anesthetic procaine is known to act in a mutually exclusive manner with the agonist self-inhibition site. We found that octanol and procaine acted as separate sites, which exhibited a negative heterotrophic interaction such that octanol reduced the affinity of procaine 6-fold. We conclude that octanol and heptanol inhibit cation flux through the channel of the nAcChoR by binding to a site (or a set of sites of equal affinity) whose location is distinct from, but allosterically coupled to, the agonist self-inhibition site.

1-Octanol↗

PubMed2026

Interpreting Mutation Co-Occurrence in Cancer Genomics Under Biological Context.

Somatic mutation patterns observed in cancer genomes are widely used to generate hypotheses about functional relationships among cancer genes and signaling pathways. However, mutation co-occurrence and mutual exclusivity are assessed at multiple levels, including cohorts, bulk specimens, lesions, regions, clones, and individual cells, although each observational level supports a different scope of inference. In this structured narrative review, we clarify these inferential boundaries and distinguish marginal from conditional association, as well as negative association from complete mutual exclusivity. A hypothetical numerical example of Simpson's reversal illustrates how marginal and conditional associations can differ and why negative association with non-zero overlap should be distinguished from complete mutual exclusivity. We then synthesize evidence from bulk, multi-region, phylogenetic, and single-cell analyses to examine spatial and clonal localization, interclonal cooperation, single-cell error and detection power, and genetic versus non-genetic resistance. We also provide a decision guide for method selection and a staged framework for functional validation. Overall, statistical association, physical localization, and functional interaction are related but distinct inferential targets that require different data, assumptions, and forms of validation.

clonal evolution↗

PubMed2026

Cooccurrence of Homologous Recombination Deficiency and Mismatch Repair Deficiency in Colorectal Cancer.

Homologous recombination deficiency (HRD) in colorectal cancer (CRC) remains largely unexplored. In contrast, mismatch repair deficiency (dMMR) occurs in ∼15% of patients with CRC. Although HRD and dMMR have historically been regarded as mutually exclusive, emerging evidence suggests that this mutual exclusivity may not be absolute. Here, we conducted a retrospective cohort study utilizing genomic and transcriptomic data to define HRD status in a Chinese dMMR CRC cohort (n = 99). Multiple machine learning approaches were employed to analyze the expression profiles of these tumors and to develop a classifier distinguishing HRD from homologous recombination proficiency (HRP) in dMMR CRCs. In the Chinese dMMR CRC cohort, 66% of tumors were classified as HRD. Compared with the HRP group, the HRD group had a significantly higher tumor mutational burden and better outcomes. The derived expression signature, comprising eight genes, successfully predicted HRD status in dMMR tumors with high accuracy in the training set (AUC = 0.88, Naïve Bayes) and the test set (AUC = 0.87). In this study, a subset of dMMR CRC tumors with co-occurring HRD was identified, which may have potential implications for patient stratification and the application of targeted therapies, such as PARP inhibitors, in this molecular subgroup.

colorectal cancer↗

PubMed1989

Developmental and muscle-specific regulation of avian fast skeletal troponin T isoform expression by mRNA splicing.

We have investigated the developmental regulation of the avian fast skeletal muscle troponin T (TnTf) gene of the Japanese quail. Sequence analysis of troponin T mRNA, cDNA clones, and a genomic DNA segment demonstrate that the avian, fast skeletal TnTf protein isoforms are produced from a single gene. This TnTf gene is expressed in skeletal muscle, but not in adult cardiac muscles or in non-muscle tissues. In addition to known TnT isoforms, three new isoforms of TnT are described. These isoforms arise by regulated alternative RNA splicing of exons in the 5' and 3' regions of TnTf transcripts. Alternative splicing of the 5' TnTf exons involves splicing of multiple exons in different combinations (i.e. not mutually exclusive), whereas 3' alternative splicing involves mutually exclusive splice choices between two exons (alpha or beta exons). S1 nuclease protection and primer extension analyses show that alternative splicing of both 5' and 3' exons is precisely regulated and coordinated in physiologically different striated muscles, which express distinct, restricted combinations of 5' and 3' alternatively spliced exons in mRNA transcripts. In contrast, different embryonic muscles and clonal embryonic myoblast cultures coexpress the 3' alternative splice choices. This indicates that alternative splicing of TnTf mRNAs is controlled in different adult muscles by specific trans factors, and not by the restricted expression of different spliced forms in different embryonic myoblast lineages. Comparison of TnTf isoform expression in quail and chicken flight muscle (Wilkinson, J. M., Moir, A. J., and Waterfield, M. D. (1984) Eur. J. Biochem. 143, 47-56) to TnTf isoforms of the rat (Breitbart, R. E., and Nadal-Ginard, B. (1986) J. Mol. Biol. 188, 313-324), and rabbit (Pearlstone, J. R., Carpenter, M. R., and Smillie, M. B. (1976) Proc. Natl. Acad. Sci. U. S. A. 73, 1902-1906) indicates that the avian gene contains an additional exon(s) not present in mammalian genes. The alternative exon sequences TnTf mRNAs expressed in anatomically distinct quail muscles can be correlated with sequences in TnTf protein isoforms in these chicken muscles. Thus, the regulated splicing of alternative exons in TnT transcripts, and not selective translation of stochastically spliced TnT mRNAs, regulates TnTf isoform expression in specific muscles.

Aging↗

PubMed2005

Exploration of genetic alterations in human endometrial cancer and melanoma: distinct tumorigenic pathways that share a frequent abnormal PI3K/AKT cascade.

Mutations of RAS, RAF, and PTEN, all important members of the RAS/MAPK and PI3K/AKT cascades, are reported in a variety of human tumors, including melanomas and endometrial cancer. In endometrial cancer, mutually exclusive mutations of PTEN and KRAS have been reported. On the other hand, mutation of BRAF is highly frequent, and mutually exclusive mutations of BRAF and NRAS have also been reported in melanomas. In this study, we elucidated the involvement of the up-regulation of RAS/MAPK and PI3K/AKT cascades in the pathogenesis of endometrial cancer and melanoma by analyzing the genes and molecules in these cascades. Twelve cell lines, six melanoma and six endometrial cancer, were analyzed; 4 (67%) of the 6 melanomas had gene mutations in the RAS/MAPK cascade, and a decrease or loss of PTEN expression was also observed. These results suggested that simultaneous up-regulations in these two cascades play important roles in carcinogenesis of melanocytes. However, no activation of AKT by phosphorylation was observed. On the other hand, 4 (67%) of the 6 endometrial cancer cell lines had mutually exclusive up-regulations in these cascades. However, two cell lines with up-regulation of the PI3K/AKT cascade also had up-regulation in the RAS/MAPK cascade induced by inactivation of DUSP6. These results suggest that simultaneous up-regulation of RAS/MAPK and PI3K/AKT cascades are crucial events in the pathogenesis of melanocytes, whereas up-regulation of either the RAS/MAPK or PI3K/AKT cascade is crucial for the majority of endometrial cancers.

Base Sequence↗

PubMed2000

Alteration in p53 modulates glial proteins in human glial tumour cells.

In transformed human glial cells, abnormalities of the p53 gene and altered expression of glial-specific properties (GSPs) have been observed. We therefore investigated whether (i) expression of the altered p53 protein is involved in the reduced expression of GSPs; and (ii) expression of the wild-type p53 (wt-p53) gene leads to induction of GSPs. We first determined that the p53 gene is mutated in human glioblastoma U-373MG cells. In these cells, and in human T-98G glioblastoma cells reported to possess a mutated p53 (m-p53) gene, nuclear m-p53 expression was intense while GSP expression was low in the same cell as revealed by double labelling immunocytochemistry. Conversely, glial fibrillary acidic protein (GFAP) and glutamate synthase (GS) were expressed in cells devoid of nuclear m-p53 immnunoreactivity. Therefore, a mutually exclusive relationship exists between the cytoplasmic GSPs and nuclear m-p53. Upon treatment with retinoic acid (RA) and dibutyryl cyclic AMP (dbcAMP), overall GSP staining were increased concomitant with suppression of nuclear m-p53. Their mutually exclusive expression pattern was maintained suggesting a functional relationship. This is supported by the observation of a similar mutually exclusive expression pattern for p53 and GSPs in pathologic specimens of human glioblastoma tissues. We then explored the role of the wt-p53 gene in the induction of GSPs using a wt-p53 tetracycline-regulated conditional expression system in human LN-Z308 glioblastoma cells. These cells normally express no p53 and no appreciable levels of GS or GFAP. Induced expression of wt-p53 lead to induction of GSP. These observations are consistent with the hypotheses that (i) nuclear m-p53 expression and cytoplasmic expression of GFAP and GS are inversely correlated, and (ii) expression of the wt-p53 gene leads to the expression of GSPs.

Amino Acid Sequence↗

PubMed2000

Gating of store-operated channels by conformational coupling to ryanodine receptors.

We report here that RyRs interact with and gate the store-operated hTrp3 and Icrac channels. This gating contributes to activation of hTrp3 and Icrac by agonists. Coupling of hTrp3 to IP3Rs or RyRs in the same cells was found to be mutually exclusive. Biochemical and functional evidence suggest that mutually exclusive coupling reflects clustering and segregation of hTrp3-IP3R and hTrp3-RyR complexes in plasma membrane microdomains. Gating of CCE by RyRs indicates that gating by conformational coupling is not unique to skeletal muscle but is a general mechanism for communication between events in the plasma and endoplasmic reticulum membranes.

Barium↗

PubMed1990

Myosin light-chain 1/3 gene alternative splicing: cis regulation is based upon a hierarchical compatibility between splice sites.

The mechanisms involved in the selective joining of appropriate 5' and 3' splice sites are still poorly understood in both constitutive and alternatively spliced genes. With two promoters associated with different exons, the myosin light-chain 1/3 gene generates two pre-mRNAs that also differ by the use of a pair of internal exons, 3 and 4, that are spliced in a mutually exclusive fashion. When the promoter upstream from exon 1 is used, only exon 4 is included. If the promoter upstream from exon 2 is used, only exon 3 is included. In an attempt to understand the molecular basis for the mutually exclusive behavior of these two exons and the basis of their specific selection, a number of minigene constructs containing exons 3 and 4 were tested in a variety of homologous or heterologous cis and trans environments. The results demonstrate that the mutually exclusive behavior of myosin light-chain exons 3 and 4 and selection between the two exons are cis regulated and are affected by the nature of the flanking sequences. Both exons competed for the common flanking 5' and 3' splice sites. Flanking exons were found that favored inclusion into mature mRNA of exon 3, exon 4, both, or neither, suggesting a specific cooperative interaction between certain 5' and 3' splice sites. Thus, alternative splicing of myosin light-chain 1/3 pre-mRNAs is regulated in cis by a hierarchy of compatibilities between pairs of 5' and 3' splice sites.

Animals↗

PubMed1990

Mycophenolic acid and thiazole adenine dinucleotide inhibition of Tritrichomonas foetus inosine 5'-monophosphate dehydrogenase: implications on enzyme mechanism.

Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the oxidation of inosine 5'-monophosphate (IMP) to xanthosine 5'-monophosphate (XMP) with the conversion of NAD to NADH. An ordered sequential mechanism where IMP is the first substrate bound and XMP is the last product released was proposed for Tritrichomonas foetus IMPDH on the basis of product inhibition studies. Thiazole adenine dinucleotide (TAD) is an uncompetitive inhibitor versus IMP and a noncompetitive inhibitor versus NAD, which suggests that TAD binds to both E-IMP and E-XMP. Mycophenolic acid is also an uncompetitive inhibitor versus IMP and noncompetitive versus NAD. Multiple-inhibitor experiments show that TAD and mycophenolic acid are mutually exclusive with each other and with NADH. Therefore, mycophenolic acid most probably binds to the dinucleotide site of T. foetus IMPDH. The mycophenolic acid binding site was further localized to the nicotinamide subsite within the dinucleotide site: mycophenolic acid was mutually exclusive with tiazofurin, but could form ternary enzyme complexes with ADP or adenosine diphosphate ribose. NAD inhibits the IMPDH reaction at concentrations greater than 3 mM. NAD substrate inhibition is uncompetitive versus IMP, which suggests that NAD inhibits by binding to E-XMP. TAD is mutually exclusive with both NAD and NADH in multiple-inhibitor experiments, which suggests that there is one dinucleotide binding site. The ordered mechanism predicts that multiple-inhibitor experiments with XMP and TAD, mycophenolic acid, or NAD should have an interaction constant (alpha) between 0 and 1. However, alpha was greater than 1 in all cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine Nucleotides↗

PubMed1987

Applications of cost-benefit analysis to health care. Departures from welfare economic theory.

In applying the principles of cost-benefit analysis to real world problems of resource allocation particular care must be taken to ensure that the welfare economic theory which underlies the cost-benefit technique is adhered to. Major problems arise where costs and benefits are used interchangeably to represent the good and bad attributes of a programme. Furthermore, in the presence of mutually exclusive projects, focussing attention upon the net benefits (or cost-benefit ratios) of individual projects as opposed to the net benefits of the use of budgeted resources can lead to biased estimates of the shadow price of projects and, consequently, errors in analysts' conclusions. As a result, economic appraisals of individual projects are not directly relevant for choosing between mutually exclusive projects of different sizes. Both types of problem are illustrated by reference to both simple examples and published economic appraisals of health care techniques. Integer programming is proposed and demonstrated as a method of selecting between mutually exclusive projects.

Budgets↗

PubMed1992

cis-acting sequences involved in exon selection in the chicken beta-tropomyosin gene.

The chicken beta-tropomyosin gene contains an internal pair of mutually exclusive exons (6A and 6B) that are selected in a tissue-specific manner. Exon 6A is incorporated in fibroblasts and smooth muscle cells, whereas exon 6B is skeletal muscle specific. In this study we show that two different regions in the intron between the two mutually exclusive exons are important for this specific selection in nonmuscle cells. Sequences in the 3' end of the intron have a negative effect in the recognition of the 3' splice site, while sequences in the 5' end of the intron have a positive effect in the recognition of the 5' splice site. First, sequences in exon 6B as well as in the intron upstream of exon 6B are both able to inhibit splicing when placed in a heterologous gene. The sequences in the polypyrimidine stretch region contribute to splicing inhibition of exons 5 or 6A to 6B through a mechanism independent of their implication in the previously described secondary structure around exon 6B. Second, we have identified a sequence of 30 nucleotides in the intron just downstream of exon 6A that is essential for the recognition of the 5' splice site of exon 6A. This is so even after introduction of a consensus sequence into the 5' splice site of this exon. Deletion of this sequence blocks splicing of exon 6A to 6B after formation of the presplicing complex. Taken together, these results suggest that both the mutually exclusive behavior and the choice between exons 6A and 6B of the chicken beta-tropomyosin gene are trans regulated.

Animals↗

PubMed2005

Kinetic characterization of tetrapropylammonium inhibition reveals how ATP and Pi alter access to the Na+-K+-ATPase transport site.

Current models of the Na(+)-K(+)-ATPase reaction cycle have ATP binding with low affinity to the K(+)-occluded form and accelerating K(+) deocclusion, presumably by opening the inside gate. Implicit in this situation is that ATP binds after closing the extracellular gate and thus predicts that ATP binding and extracellular cation binding to be mutually exclusive. We tested this hypothesis. Accordingly, we needed a cation that binds outside and not inside, and we determined that tetrapropylammonium (TPA) behaves as such. TPA competed with K(+) (and not Na(+)) for ATPase, TPA was unable to prevent phosphoenzyme (EP) formation even at low Na(+), and TPA decreased the rate of EP hydrolysis in a K(+)-competitive manner. Having established that TPA binding is a measurement of extracellular access, we next determined that TPA and inorganic phosphate (P(i)) were not mutually exclusive inhibitors of para-nitrophenylphosphatase (pNPPase) activity, implying that when P(i) is bound, the transport site has extracellular access. Surprisingly, we found that ATP and TPA also were not mutually exclusive inhibitors of pNPPase activity, implying that when the cation transport site has extracellular access, ATP can still bind. This is consistent with a model in which ATP speeds up the conformational changes that lead to intracellular or extracellular access, but that ATP binding is not, by itself, the trigger that causes opening of the cation site to the cytoplasm.

4-Nitrophenylphosphatase↗

PubMed1972

Gene selection in hemoglobin and in antibody-synthesizing cells.

Close linkage of mutually exclusive genes occurs in the non-alpha chain hemoglobin genes and in the immunoglobulin genes of man and other mammals. The expression of one gene in the cluster precludes the expression of any other linked gene. A simple, testable theory of gene selection called "looping-out excision"which was designed only to explain this mutual exclusivity in the hemoglobin system is described. The theory is closely concordant with a wide range of previously unexplained findings concerning hematopoiesis- including the developmental changes of hemoglobins, the increases in immature or fetal forms of hemoglobin that accompany anemia, and with the distribution of adult and fetal hemoglobins among erythrocytes during normal embryogenesis and in various pathological conditions. One corollary of this theory is that erythroid tissue in the normal adult bone marrow is constantly recapitulating the developmental stages of its embryogenesis. Another corollary is that the selection from among the linked globin genes occurs independently on the two chromosomes of the diploid organism. Both of these corollaries are supported by the available data. The same theory of gene selection is also remarkably consistent with known data for immunoglobulin synthesis; it could explain not only the mutually exclusive activation of linked variable genes but also the splicing which occurs between genetically linked variable and constant region genes for the immunoglobulin polypeptide chains. The agreement between these two different tissues is considered to be strong evidence that the proposed mechanism is correct at least in broad outline. Evidence from the genetics of maize and of drosophila also supports this theory of somatic tissue variegation. On the basis of these comparisons, I suggest that looping-out excision probably occurs also in other tissues and may be one means of gene selection and activation in differentiating cells.

Alleles↗

PubMed2003

Auditory-evoked magnetic field codes place of articulation in timing and topography around 100 milliseconds post syllable onset.

This study demonstrates by means of magnetic source imaging how consonants and vowels that constitute a syllable differently affect the neural processing within the auditory cortex. We recently identified a topographically separate processing for mutually exclusive place features in isolated vowels (Obleser et al., in press). Does this mapping principle also hold for stop consonants with differing places of articulation? How is the N100m response to consonant-vowel (CV) syllables affected by the congruency of place information in the consonant and the vowel? Moreover, how is the N100m affected by coarticulation, i.e., the spreading of place features to adjacent phonemes? By systematically varying phonological information in the consonant as well as in the vowel of CV syllables, we were able to reveal a difference in N100m syllable source location along the anterior-posterior axis due to mutually exclusive places of articulation in the vowel of the syllable. We also found a change in source orientation rather than source location due to the same mutually exclusive features in the onset of the syllable. Furthermore, the N100m time course of the brain response delivered important complementary information to identify the phonological features present in the speech signal. Responses to all syllable categories originated in the perisylvian region anterior to the source of a band-passed noise stimulus. The systematic variation of both consonantal and vocalic place features and the study of their interaction on auditory processing proves to be a valuable method to gain more insight into the elusive phenomenon of human speech recognition.

Adult↗

PubMed1998

Pregnancies complicated by retained placenta: sex ratio and relation to pre-eclampsia.

Pre-eclampsia and placenta accreta have opposite histological features of placentation. This study set out to test the hypotheses that the sex ratios in these two pregnancy complications are opposite and that these conditions are mutually exclusive. A population-based database covering all deliveries in South Australia between 1986 and 1995 and the hospital-based obstetric database of the Adelaide Women's and Children's Hospital, covering 8549 births between 1993 and 1995, were used to ascertain the sex ratios in singleton pregnancies and the sex ratios in those pregnancies in which there was retained placenta, hypertension in pregnancy, or pre-eclampsia. The likelihood of independence of occurrence or mutual exclusivity of retained placenta and hypertension in pregnancy or pre-eclampsia were also examined. The male:female sex ratio in the South Australian population was 1.077. In pregnancies with hypertension in pregnancy it was 1.165 (P<0.001) and in pregnancies with retained placenta it was 0.883 (P<0.0001). There was a trend to an increased sex ratio in pre-eclamptic pregnancy (1.248 in primigravid and 1.092 in multigravid women) but there was insufficient power to detect significance (P=0.207 and 0.470, respectively). Neither hypertension in pregnancy nor pre-eclampsia were mutually exclusive of placenta accreta: hypertensive disorders of pregnancy and placenta accreta occurred independently of each other. Our findings suggest that sex-linked antigens are unlikely to influence maternofetal interactions consistently to give rise to one but not the other pregnancy complication.

Adult↗

PubMed1994

DNA sequence requirements for the regulation of immobilization antigen A expression in Paramecium tetraurelia.

The Paramecium surface proteins (immobilization antigens) are expressed in a mutually exclusive manner; only one antigen is found on the cell surface at a time. Expression of these proteins is regulated in response to environmental cues such as temperature and pH. This regulation has been shown to be controlled at the level of mRNA abundance by transcriptional and post-transcriptional mechanisms. Here, we have studied the transcription and regulated expression of the immobilization antigen A gene in Paramecium tetraurelia by transforming an A-deficient strain, d12, with cloned portions of the A gene via microinjection. The A gene is approximately 8 kilobases (kb) long with the transcription start site at position -9 or -8 and the start of translation at position +1. Paramecia transformed with cloned DNA containing A-gene sequences beginning at position -264 and ending 63 base pairs (bp) past the gene's polyadenylation site show properly regulated expression of immobilization antigen A. Lines derived from paramecia transformed with a plasmid containing A-gene sequences starting at position -211, however, show markedly reduced A-gene mRNA levels, and rarely express the A antigen. Nevertheless, cells that do express the A protein exhibit mutual exclusion and normal responses to environmental stimuli. Thus, the 54 bp between -264 and -211, while important for transcription, are not involved in the control of mutual exclusion and responses to environmental changes. Further deletion to position -151 yields similar, but more extreme, results.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Steroids and growth promoting factors in the regulation of expression of genes and gene networks.

Steroid hormones and growth promoting factors regulate the expression of a number of genes involved in cellular growth and differentiation. In many cases, cellular proliferation and differentiation-specific pathways are mutually exclusive. As an example for the mechanism of mutual exclusion, transcription factors responsible for pathway-specific gene expression interact with each other. Steroid hormone receptors inhibit the action of the transcription factor AP-1 (Fos/Jun) and vice versa. This inhibitory interaction is predominantly effected at the level of protein-protein contact without the need for the interfering transcription factor to bind to DNA. In some cases the two pathways function additively or even synergistically resulting in cooperation of the transcription factors in regulation of gene expression. The examples to be discussed in this text document how elaborate and important cross-talks between signal transduction pathways are. This is particularly demonstrated by the fine tuning and reversibility of these processes.

Animals↗

PubMed2002

Role of N-cadherin- and integrin-based costameres in the development of rat cardiomyocytes.

Costameres, vinculin-containing structures found in skeletal and cardiac muscle, are thought to anchor the Z-discs of the peripheral myofibrils to the sarcolemma. Several lines of evidence indicate that two different sets of costameres, integrin- and N-cadherin-based, are present in cardiac muscles. In this study, immunoblot analysis was used to study the expression of N-cadherin, alpha-catenin, beta-catenin, vinculin, talin, and laminin in rat cardiac muscles at embryonic days 15 and 19, the day of birth (postnatal day 0), postnatal weeks 1, 2, 3, and 4, and in the adult. Double immunofluorescence microscopy was performed to study the spatial and temporal distribution of these two sets of costameres in rat cardiomyocytes. Costameric staining for N-cadherin, codistributed with beta-catenin, was strong from embryonic day 15 up to postnatal week 2, gradually decreased after postnatal week 3, and was undetectable at postnatal week 4 and in the adult. Confocal microscopy showed that N-cadherin colocalized with alpha-actinin at cortical myofibrils. Double-labeling of beta-catenin and talin indicated the coexistence of N-cadherin/catenin- and integrin/talin-based costameres in rat cardiac muscle. Although beta-catenin and vinculin were co-localized at the costamere of cardiomyocytes from embryonic day 15 to postnatal week 3, staining for beta-catenin or talin was mutually exclusive at all stages examined. These results demonstrate the simultaneous, but mutually exclusive, existence of N-cadherin/catenin- and integrin/talin-based costameres in rat cardiomyocytes between late embryonic stages and postnatal week 3, while only integrin/talin-based costameres were found in adult rats. The N-cadherin/catenin-based costameres in rat cardiac muscles may play a role in myofibrillogenesis similar to that of their counterparts in cultured cardiomyocytes.

Animals↗