A Novel Genetic Pathway for Sudden Cardiac Death via Defects in the Transition between Ventricular and Conduction System Cell Lineages

Nguyên-Trân, Vân; Kubalak, Steven W.; Minamisawa, Susumu; Fiset, Céline; Wollert, Kai C.; Brown, Anne B.; Ruiz‐Lozano, Pilar; Barrère-Lemaire, Stéphanie; Kondo, Richard P.; Norman, Lisa W.; Gourdie, Robert G.; Rahme, Marc M.; Feld, Gregory K.; Clark, Robert B.; Giles, Wayne R.; Chien, Kenneth R.

doi:10.1016/s0092-8674(00)00089-1

Cited by 127 publications

(88 citation statements)

References 35 publications

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“…Although the Sp4 null mutant mice suffered from cardiac arrhythmia and cardiac sudden death (about 40% lethality), 7 extensive ECG analysis on eight pairs of hypomorphic Sp4 mutant mice demonstrated normal heart rates without bradycardia, suggesting that the hypomorphic Sp4 mice did not suffer an ischemic event (data not shown). Moreover, CA1, the hippocampal subregion most sensitive to ischemia, appeared normal in hypomorphic Sp4 mutant mice.…”

Section: Hippocampal Vacuolizationmentioning

confidence: 96%

“…The subsequent fixation, permeabilization and staining were performed as described previously. 7 For pathological analysis of the Sp4 mutant hippocampus, 10 mm paraffin sections were used. All mouse brains were taken without perfusion and immediately fixed in 4% paraformaldehyde solution for at least 24 h. Subsequent dehydration and paraffin embedding were performed as described.…”

Section: Histological and Immunohistochemical Analysismentioning

confidence: 99%

“…All mouse brains were taken without perfusion and immediately fixed in 4% paraformaldehyde solution for at least 24 h. Subsequent dehydration and paraffin embedding were performed as described. 7 Hematoxylin-eosin staining was used for the detection of pathological abnormalities in mutant hippocampus. A modified Timm's staining was performed to detect hippocampal mossy fibers as described elsewhere.…”

Section: Histological and Immunohistochemical Analysismentioning

confidence: 99%

“…13 RNA in situ hybridization and Western blot analysis RNA in situ experiments were performed using 35 S-labeled antisense neurotrophin-3 probe on 10 mm paraffin sections as described elsewhere. 7 Anti-human neurotrophin-3 antibody, crossreactive with mouse neurotrophin-3, was obtained from Promega. Anti-synaptophysin monoclonal antibody was purchased from Chemicon.…”

Section: Electron Microscopic Analysesmentioning

confidence: 99%

“…6 Previously, we found that HF-1b/ Sp4 null mutant mice suffer from cardiac arrhythmia and sudden death. 7 Although Sp4 has some role in heart development, it is expressed predominantly in the developing nervous system. 8,9 As yet, the specific role of Sp4 in the nervous system remains to be determined.…”

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confidence: 99%

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Reduced expression of the Sp4 gene in mice causes deficits in sensorimotor gating and memory associated with hippocampal vacuolization

et al. 2004

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Hf-1b/Sp4, a member of the Sp1 family of transcription factors, is expressed restrictively in the developing nervous system and most abundantly in adult hippocampus in mice. Here, we report the generation of hypomorphic Sp4 allele mice, in which the Sp4 deficiency can be rescued by the expression of Cre recombinase. Vacuolization was detected in the hippocampal gray matter of the mutant Sp4-deficient mice. Expression analysis of Sp4 mutant hippocampi revealed an age-dependent decrease in neurotrophin-3 expression in the dentate granule cells. Hypomorphic Sp4 mutant mice displayed robust deficits in both sensorimotor gating and contextual memory. The restoration of Sp4 expression, via a Cre-dependent rescue strategy, completely rescued all the observed molecular, histological and behavioral abnormalities. Our studies thus reveal a novel Sp4 pathway that is essential for hippocampal integrity and modulates behavioral processes relevant to psychiatric disorders. Molecular Psychiatry ( Keywords: transcription factor; hippocampus; schizophrenia; mouse model; behavior; Cre recombinase; genetic rescue Sp1, the prototypal member of the Sp family of transcription factors, has been demonstrated to be essential for embryogenesis. 1 The reduction of its expression in heterozygous Sp1 mice causes a decreased expression of its downstream target gene, MeCP2, whose mutation is responsible for Rett syndrome, a human neurodevelopmental disorder. 2 Recently, Sp1 and other glutamine-rich transcription factors have been implicated in the pathogenesis of neurodegenerative diseases. 3,4 Sp4, also known as HF1b, is another member of the Sp1 family of transcription factors. Sp1 and Sp4 proteins have approximately 50% homology in primary structure, which consists of two glutamine-rich transcription activation domains and Cterminal three zinc-finger DNA binding domains. 5 Both proteins recognize the same DNA binding motif with similar affinity, and often functionally substitute for each other in vitro. 6 Previously, we found that HF-1b/ Sp4 null mutant mice suffer from cardiac arrhythmia and sudden death. 7 Although Sp4 has some role in heart development, it is expressed predominantly in the developing nervous system. 8,9 As yet, the specific role of Sp4 in the nervous system remains to be determined.In our endeavor to understand the function of HF-1b/Sp4 in the nervous system, we have undertaken a genetic rescue strategy to generate hypomorphic Sp4 alleles. Targeted transgenes were designed to enable the restoration of the expression of the Sp4 gene in the context of its endogenous locus in order to rescue any abnormal in vivo phenotypes. The generated hypomorphic Sp4 allele mice were grossly normal and displayed no increased lethality. Unexpectedly, the mutant mice displayed both vacuolization in the hippocampus and abnormal behavioral phenotypes, particularly with regard to contextual memory and sensorimotor gating deficits. Hence, these studies suggest a new molecular pathway involving the Sp4 gene that functions within the hippocampu...

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Section: Hippocampal Vacuolizationmentioning

confidence: 96%

Section: Histological and Immunohistochemical Analysismentioning

confidence: 99%

Section: Histological and Immunohistochemical Analysismentioning

confidence: 99%

Section: Electron Microscopic Analysesmentioning

confidence: 99%

mentioning

confidence: 99%

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Reduced expression of the Sp4 gene in mice causes deficits in sensorimotor gating and memory associated with hippocampal vacuolization

et al. 2004

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Genetic aspects of arrhythmias

Roberts

Brugada

2000

Am. J. Med. Genet.

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Advances in the treatment and prevention of heart disease have led to consistently declining morbidity and mortality rates over the past 30 years. Despite these advances, therapy remains largely palliative. The development of curative therapies is limited by our lack of knowledge of the basic mechanisms of disease. In the next decade, we will probably change many of these current approaches from treating the crisis to preventing the disease. Molecular biology and genetics have elucidated several basic pathways. It is hoped that targeted therapies will prevent or arrest many of these cardiac diseases, in particular, arrhythmias and sudden death. With the discovery of the genes causing familial diseases like long QT, hypertrophic cardiomyopathy, and Brugada syndrome, we have identified several substrates responsible for triggering malignant arrhythmias.

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Transitions in ventricular activation revealed by two‐dimensional optical mapping

et al. 2004

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While cardiac function in the mature heart is dependent on a properly functioning His-Purkinje system, the early embryonic tubular heart efficiently pumps blood without a distinct specialized conduction system. Although His-Purkinje system precursors have been identified using immunohistological techniques in the looped heart, little is known whether these precursors function electrically. To address this question, we used high-resolution optical mapping and fluorescent dyes with two CCD cameras to describe the motion-corrected activation patterns of 76 embryonic chick hearts from tubular stages (stage 10) to mature septated hearts (stage 35). Ventricular activation in the tubular looped heart (stages 10 -17) using both calcium-sensitive fluo-4 and voltage-sensitive di-4-ANEPPS shows sequentially uniform propagation. In late looped hearts (stages 18 -22), domains of the dorsal and lateral ventricle are preferentially activated before spreading to the remaining myocardium and show alternating regions of fast and slow propagation. During stages 22-26, action potentials arise from the dorsal ventricle. By stages 27-29, action potential breakthrough is also observed at the right ventricle apex. By stage 31, activation of the heart proceeds from foci at the apex and dorsal surface of the heart. The breakthrough foci correspond to regions where putative conduction system precursors have been identified immunohistologically. To date, our study represents the most detailed electrophysiological characterization of the embryonic heart between the looped and preseptated stages and suggests that ventricular activation undergoes a gradual transformation from sequential to a mature pattern with right and left epicardial breakthroughs. Our investigation suggests that cardiac conduction system precursors may be electrophysiologically distinct and mature gradually throughout cardiac morphogenesis in the chick.

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A Novel Genetic Pathway for Sudden Cardiac Death via Defects in the Transition between Ventricular and Conduction System Cell Lineages

Cited by 127 publications

References 35 publications

Reduced expression of the Sp4 gene in mice causes deficits in sensorimotor gating and memory associated with hippocampal vacuolization

Reduced expression of the Sp4 gene in mice causes deficits in sensorimotor gating and memory associated with hippocampal vacuolization

Genetic aspects of arrhythmias

Transitions in ventricular activation revealed by two‐dimensional optical mapping

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