抄録
The HST-1 gene, originally identified in our laboratory as a transforming gene, encodes HST-1 protein or fibroblast growth factor (FGF)-4, a member of the FGF family. In this study, to explore a novel function of HST-1 gene, gene knock-in (gain of function) and knock-out (loss of function) were performed.
To identify the target cells and tissues which are susceptible to the biological actions of HST-I protein in vivo, we gave mice a recombinant adenovirus carrying the HST-l gene (AdexHST-l). The results show that AdexHST-l caused a two-fold increase in peripheral platelet count for a period of 30 days, and also effectively prevented experimentally induced thrombocytopenia. We further elucidated that thrombopoietic action of HST-1 is achieved in that HST-1 can regulate megakaryocyte development as a megakaryocyte potentiator synergistically with IL-3 and TPO as well as potentiates magakaryocyte maturation.
As a means of exploring the role of HST- I in vertebrate embryogenesis, mice with distrupted HST-1 gene were produced by homologous recombination. Null mutant ES cells survived but homozygous HST-1-/- mutants showed severe develop-mental delay and died before 9 days of gestation, suggesting that HST-l plays essential roles in early phases of mouse development.
In addition to its early embryonic function, HST-1 may play a crucial role in the later stage of development. In fact, we and others have found that HST-1 is expressd in the cells of the apical ectodermal ridge of mouse limb bud at 11 and 12 days of gestation. In an effort to further understand the role of HST-l in mouse limb development, we initially established a novel limb culture system which provides us with a suitable model system to explore the key factors for limb development. Using this culture system, we have shown that exposure of embryonal limb bud explants to antisense oligonucleotides of HST-1 blocks limb outgrowth. Our results suggest direct evidence that HST-1 worked naturally as an inducer of mouse limb development.
