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F J Mangiacapra

Publications and source records attributed to F J Mangiacapra.

5 recordsLinked to original sources
PubMed1995

Activin A and transforming growth factor-beta stimulate heart formation in axolotls but not rescue cardiac lethal mutants.

In the Mexican axolotl (salamander), Ambystoma mexicanum, a recessive cardiac lethal mutation causes an incomplete differentiation of the myocardium. Mutant hearts lack organized sarcomeric myofibrils and do not contract throughout their lengths. We have previously shown that RNA purified from normal anterior endoderm or from juvenile heart tissue is able to rescue mutant embryonic hearts in an in vitro organ culture system. Under these conditions as many as 55% of formerly quiescent mutant hearts initiate regular contractions within 48 hours. After earlier reports that transforming growth factor-beta 1 and, to a lesser extent, platelet-derived growth factor-BB could substitute for anterior endoderm as a promoter of cardiac mesodermal differentiation in normal axolotl embryos, we decided to examine the effect of growth factors in the cardiac mutant axolotl system. In one type of experiment, stage 35 mutant hearts were incubated in activin A, transforming growth factors-beta 1 or beta 2, platelet-derived growth factor, or epidermal growth factor, but no rescue of mutant hearts was achieved. Considering the possibility that growth factors would only be effective at earlier stages of development, we tested transforming growth factors-beta 1 and beta 5, and activin A on normal and mutant precardiac mesoderm explanted in the absence of endoderm at neurula stage 14. We found that, although these growth factors stimulated heart tube formation in both normal and mutant mesoderm explants, only normal explants contained contractile myocardial tissue. We hypothesize that transforming growth factor-beta superfamily peptides initiate a cascade of responses in mesoderm that result in both changes in cell shape (the basis for heart morphogenesis) and terminal myocardial cytodifferentiation. The cardiac lethal mutation appears to be deficient only in the latter process.

Activins↗
PubMed1995

The cardiac mutant gene c in axolotls: cellular, developmental, and molecular studies.

The cardiac mutant axolotl is an interesting model for studying heart development. The mutant gene results in a failure of heart cells to form organized myofibrils and as a consequence the heart fails to beat. Experiments have shown that mutant hearts can be "rescued" (i.e., turned into normally contracting organs) by the addition of RNA purified from conditioned media produced by normal embryonic anterior endoderm-mesoderm cultures. These corrected hearts form myofibrils of normal morphology. New advances in recombinant DNA technology applied to this system should provide significant insights into the regulatory mechanisms of myofibrillogenesis as well as the inductive processes related to the control of gene expression during embryonic heart development. In a broader biological sense, the use of gene c in axolotls is potentially capable of helping to solve major unanswered questions in modern biology related to the genetic regulation of differentiation in vertebrates.

Ambystoma↗
PubMed1993

IGFs and muscle differentiation.

The Role of IGFs in Myogenesis. Thus we are now convinced that the control of myogenesis by IGFs is a general phenomenon that occurs in all skeletal muscle cells, whether or not IGFs are added to the "differentiation" medium. We believe that several medium components contribute to the suppression of IGF-II expression in myoblasts incubated in high serum "growth" medium, and conclude that the IGF-I receptor mediates the feedback inhibition of IGF-II gene expression in muscle cells. Mechanism of Induction of Myogenesis by IGFs. The observations summarized here now permit a reasonably coherent overview of the stimulation of myogenic differentiation by the IGFs. It seems clear that all IGFs act by binding to the Type I IGF receptor, and that this process is inhibited to a significant extent by IGF binding proteins secreted by the target myoblasts. A major, but possibly not the only relevant effect of this binding is the induction of expression of the myogenin gene; this induction appears to require the presence of myf-5 protein, at least during the early part of the response. Cells capable of a mitogenic response undergo a round of division in response to IGF-I, thus delaying their entry into the final processes of postmitotic terminal differentiation. Other laboratories have shown that myogenin complexes with one or more widely occurring proteins such as E12 or E47 to form an active complex that interacts with CAnnTG elements in muscle specific genes, turning on expression of those genes and thus initiating the phenotype associated with terminally differentiated skeletal muscle.

Animals↗
PubMed1992

Paradoxical decrease in myf-5 messenger RNA levels during induction of myogenic differentiation by insulin-like growth factors.

Having previously demonstrated that the insulin-like growth factors (IGFs) induce expression of the myogenin gene, we have now extended our investigation of the induction of myogenesis by the IGFs to a second member of the MyoD family, myf-5. This is the only myogenesis gene other than myogenin expressed early in the differentiation of L6 myoblasts, so its regulation was of particular interest because of our observations on myogenin. In contrast to myogenin, myf-5 mRNA was detectable in proliferating myoblasts, but the steady state levels of myf-5 mRNA fell strikingly for 48 h after the cells were switched to low serum medium containing IGF-II in both murine cell lines and myoblasts cultured from human muscle. In spite of this decrease, translation of myf-5 mRNA appeared essential during the early stages of stimulation of myogenesis by the IGFs; an antisense oligodeoxynucleotide complementary to the first five codons of myf-5 blocked the increase in myogenin mRNA and inhibited morphological (cell fusion) and biochemical (creatine kinase elevation) aspects of myogenesis. We conclude that expression of myf-5 is essential for the initial induction of myogenin by the IGFs, but that subsequent elevation of myogenin expression is independent of myf-5, possibly resulting from autoinduction of the myogenin gene. The functional significance of the dramatic decrease in myf-5 mRNA levels during differentiation is not obvious.

Animals↗