Sustained cardiomyocyte DNA synthesis in whole embryo cultures lacking the TSC2 gene product

Laura Pajak, Fang Jin, Guang Hui Xiao, Mark H. Soonpaa, Loren J. Field, Raymond S. Yeung

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Tuberous sclerosis complex (TSC) is characterized by the appearance of nonmalignant tumors that affect a wide spectrum of organs, including the heart. TSC disease-causing genes have been identified on chromosomes 9 (TSC1) and 16 (TSC2). This study examined the impact of the TSC2 gene product on cardiomyocyte proliferation and terminal differentiation. We took advantage of the observation that Eker rats carry a germ-line TSC2 mutation. Rats heterozygous for the mutation (TSC2(EK/+)) are predisposed to renal carcinoma, whereas animals homosygous for the mutation (TSC2(EK/EK)) die in utero during midgestation. Spontaneously contractile cardiomyocytes were observed after multiple passages of whole embryo cultures prepared from embryonic day 12.5 TSC2(EK/EK) fetuses but not from TSC2(EK/+) or wild-type fetuses. The TSC2(EK/EK) cardiomyocytes continued to actively synthesize DNA after as many as eight passages. Cytological, ultrastructural, and molecular analyses indicated that the TSC2(EK/EK) cardiomyocytes retained a highly differentiated phenotype similar to that observed for normal rat cardiomyocytes during late embryonic and early neonatal life. These results suggested that the TSC2 gene product is required for normal cardiomyocyte cell-cycle withdrawal and terminal differentiation.

Original languageEnglish (US)
Pages (from-to)H1619-H1627
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume273
Issue number3 42-3
StatePublished - Oct 13 1997

Keywords

  • Antioncogenes
  • Cardiac regeneration
  • Cardiac tumor
  • Eker rat
  • Terminal differentiation
  • Tuberin
  • Tumor suppressors

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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