Specific arrest of cardiogenesis in cultured embryonic stem cells lacking Cripto-1.
The molecular events of cardiac lineage specification and differentiation are largely unknown. Here we describe the involvement of a growth factor with an EGF-like domain, Cripto-1 (Cr-1), in cardiac differentiation. During embryonic development, Cr-1 is expressed in the mouse blastocyst, primitive streak, and later is restricted to the developing heart. To investigate the role of Cr-1, we have generated Cr-1-negative embryonic stem (ES) cell lines by homologous recombination. The resulting double "knockout" ES cells have selectively lost the ability to form beating cardiac myocytes, a process that can be rescued by reintroducing Cr-1 gene back into the Cr(-/-) cells. Furthermore, the lack of functional Cr-1 is correlated with absence of expression of cardiac-specific myosin light and heavy chain genes during differentiation. Differentiation into other cell types including skeletal muscle is not disrupted. These results suggest that Cr-1 is essential for contractile cardiomyocyte formation in vitro.
Xu
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C
Burnham Institute, La Jolla Cancer Research Center, California 92037, USA.
Liguori
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G
Adamson
E D
ED
Persico
M G
MG
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics; D004815:Epidermal Growth Factor; D005326:Fetal Proteins; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D018390:Gene Targeting; D006321:Heart / Q000196:embryology*; D008562:Membrane Glycoproteins; D008648:Mesoderm / Q000737:chemistry; D051379:Mice; D009024:Morphogenesis; D018485:Muscle Fibers, Skeletal; D018482:Muscle, Skeletal / Q000166:cytology; D009200:Myocardial Contraction; D009206:Myocardium / Q000737:chemistry / Q000166:cytology*; D018008:Myogenin / Q000235:genetics; D018995:Myosin Heavy Chains / Q000032:analysis; D018994:Myosin Light Chains / Q000032:analysis / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D016900:Neurofilament Proteins / Q000235:genetics; D009474:Neurons; D012333:RNA, Messenger / Q000032:analysis; D013234:Stem Cells / Q000737:chemistry / Q000166:cytology*; D020825:T-Box Domain Proteins; D014157:Transcription Factors / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology; D000098908:Brachyury Protein
D004268:DNA-Binding Proteins; D004815:Epidermal Growth Factor; D005326:Fetal Proteins; D008562:Membrane Glycoproteins; D018008:Myogenin; D018995:Myosin Heavy Chains; D018994:Myosin Light Chains; D009363:Neoplasm Proteins; D016900:Neurofilament Proteins; D012333:RNA, Messenger; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D014212:Tretinoin; D000098908:Brachyury Protein; C503801:Myog protein, mouse; C489450:Tdgf1 protein, mouse