Cardiac Malformation in Neonatal Mice Lacking Connexin43

Reaume, Andrew G.; Sousa, Paul A. De; Kulkarni, Surendra U.; Langille, B. Lowell; Zhu, Daguang; Davies, Tyler C.; Juneja, Subhash C.; Kidder, Gerald M.; Rossant, Janet

doi:10.1126/science.7892609

Cited by 1,160 publications

(868 citation statements)

References 42 publications

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“…Several mutations in Cx43 have previously demonstrated serious conduction abnormalities both in mouse models and in human patients 47,[52][53][54][55] . Our Tmem65 knockdown results are in line with the Cx43 deletion in mouse 30 and the Cx43 deletion in the zebrafish 56 , and suggest an essential and important function for these two interacting proteins in cardiac development/function. Indeed, in all three of these cases, changes in Ca 2 þ cycling, cell development and abnormal heart morphology were observed, highlighting the coordinated interactions and physiological roles of these two proteins.…”

Section: Discussionsupporting

confidence: 84%

“…Cx43 function is strongly regulated by its localization and protein stability [30][31][32] . Therefore, we examined Cx43 levels and localization in control and Tmem65 knockdown cells.…”

Section: Resultsmentioning

confidence: 99%

“…Cx43 is the major ventricular Cx responsible for gap junction coupling in ventricles. Mutations 47 , changes in expression 30,48 and altered post-translation modifications of Cxs 49 are the underlying mechanisms for several conditions leading to cardiac arrhythmias. Germline deletion of the Cx43 gene in mice leads to perinatal lethality due to developmental cardiac malformation 30 .…”

Section: Discussionmentioning

confidence: 99%

“…Mutations 47 , changes in expression 30,48 and altered post-translation modifications of Cxs 49 are the underlying mechanisms for several conditions leading to cardiac arrhythmias. Germline deletion of the Cx43 gene in mice leads to perinatal lethality due to developmental cardiac malformation 30 . In contrast, mice with cardiac-restricted inactivation of Cx43 are viable; however, they develop ventricular tachyarrhythmias leading to sudden cardiac death within 2 months 50,51 .…”

Section: Discussionmentioning

confidence: 99%

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Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function

et al. 2015

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Membrane proteins are crucial to heart function and development. Here we combine cationic silica-bead coating with shotgun proteomics to enrich for and identify plasma membrane-associated proteins from primary mouse neonatal and human fetal ventricular cardiomyocytes. We identify Tmem65 as a cardiac-enriched, intercalated disc protein that increases during development in both mouse and human hearts. Functional analysis of Tmem65 both in vitro using lentiviral shRNA-mediated knockdown in mouse cardiomyocytes and in vivo using morpholino-based knockdown in zebrafish show marked alterations in gap junction function and cardiac morphology. Molecular analyses suggest that Tmem65 interaction with connexin 43 (Cx43) is required for correct localization of Cx43 to the intercalated disc, since Tmem65 deletion results in marked internalization of Cx43, a shorter half-life through increased degradation, and loss of Cx43 function. Our data demonstrate that the membrane protein Tmem65 is an intercalated disc protein that interacts with and functionally regulates ventricular Cx43.

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Section: Discussionsupporting

confidence: 84%

“…Cx43 function is strongly regulated by its localization and protein stability [30][31][32] . Therefore, we examined Cx43 levels and localization in control and Tmem65 knockdown cells.…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function

et al. 2015

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“…Transfer of cAMP may amplify the transcription of cAMP-dependent steroidogenic enzymes (Payne and Youngblood, 1995) as well as synchronize testosterone release between cells of the aggregate. Directed target disruption of Cx43 gene results in mice that die early after birth from heart failure (Reaume et al, 1995). Interestingly, knock-in mice in which the Cx40-or Cx32-coding region was substituted for Cx43 survive to adulthood but show failed spermatogenesis (Plum et al, 2000).…”

Section: Bmentioning

confidence: 99%

Expression of Connexin43 in mouse Leydig, Sertoli, and germinal cells at different stages of postnatal development

et al. 2001

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Connexin 43 (Cx43) is the most abundant and ubiquitously distributed gap junction protein in testicular cells. Lack of Cx43 expression results in male infertility. We investigated whether Cx43 is expressed and regulated in Leydig, Sertoli and germinal cells at different stages of postnatal development. Cx43 was detected using three different antibodies shown by immunoblotting to be highly specific. At different postnatal ages Cx43 localization was compared in serial or double labeled testicular cryosections with immunocytochemical distribution of steroidogenic enzyme, 3 ␤hidroxysteroid-dehydrogenase (3␤HSD), Mullerian inhibitory hormone (MIH), and germinal nuclear cell antigen (GNCA1), which are specific markers of interstitial Leydig, Sertoli and germinal cells, respectively. In the interstitium, round cell clumps (RCC) with lipid droplets positive for 3␤HSD and Cx43 were frequently found at intertubular areas at birth and Cx43 was mainly localized at cell membrane appositions. From day 3, the number and size of 3␤HSD-positive RCC started to decrease, and reached a minimum at 7-14 dpp; Cx43 expressed by them is progressively downregulated. From day 21 an increase in the size and number of RCC positive for Cx43 and 3␤HSD was found that continued at 24, 26 and 28 days and reached a maximum at 35 and 60 dpp. Biphasic expression of interstitial Cx43 and 3␤HSD was also found to be positively and temporally correlated with fluctuations in intratesticular testosterone content at all ages studied. In the seminiferous cord (SC), Cx43 was expressed at birth between adjacent Sertoli cells (MIH positive) localized at the periphery, as well as in their cytoplasm projections that surround centrally localized gonocytes. From days 3 to 7, Cx43 labeling increased in Sertoli cells mainly at their apical border. At day 14, Cx43 distribution in Sertoli cells changed from apical to basal in parallel to migration of germinal (GNCA1-positive) cells from the periphery to the center of the SC. At all these ages, Cx43 was also localized at cell borders between Sertoli and germinal cells. In conclusion, this study demonstrates that Cx43 in Leydig cells is regulated during postnatal development in an age and functional dependent manner. In the tubule, it is demonstrated that Cx43 is modulated in Sertoli cells during the neonatal and prepubertal period. We also provide evidence for the first time that Cx43-gap junctions communicate between Sertoli and germinal cells before and during the first wave of spermatogenesis. Anat Rec 264: [13][14][15][16][17][18][19][20][21][22][23][24] 2001.

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De novo balanced translocation (6;18)(q21;q21.3) in a patient with heterotaxia

1996

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We report on a sporadic case of heterotaxia with a de novo chromosome structural abnormality. The patient had inversely located heart (dextrocardia), stomach, duodenum, and cecum. In addition, she had cerebral atrophy, hypertelorism with telecanthus, infraorbital skin furrows, ear-lobe grooves, prominent maxilla and teeth, large carp mouth, short fifth fingers with limited flexion, generalized hypotonicity, and severe psychomotor retardation. High-resolution chromosome banding analysis demonstrated an apparently balanced translocation: 46,XX,t(6;18)(q21;q21.3). It is hypothesized that both heterotaxia and the chromosomal abnormality in the patient are causally related and a putative situs determining gene has been disrupted by the chromosome break, i.e., a position effect or a cryptic deletion at around the breakpoints. The translocation in our patient may be a good source for positional cloning of the gene.

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Cardiac Malformation in Neonatal Mice Lacking Connexin43

Cited by 1,160 publications

References 42 publications

Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function

Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function

Expression of Connexin43 in mouse Leydig, Sertoli, and germinal cells at different stages of postnatal development

De novo balanced translocation (6;18)(q21;q21.3) in a patient with heterotaxia

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