The development of an embryo from a single fertilized egg is dependent on a succession of cellular interactions. In the early Xenopus embryo this process depends on inductive signals emanating from the vegetal embryonic pole, which cause the formation of prospective mesodermal tissues in cells of the equatorial region. Although the identity of these signals has remained obscure for many years, a growing body of evidence strongly suggests that polypeptide growth factors, such as activin and fibroblast growth factor, are likely candidates. Basic fibroblast growth factor (bFGF) is present in the early embryo and will induce mesoderm formation in vitro. Direct evidence for the requirement of FGF to form mesoderm in vivo has been lacking. Recently this laboratory has shown, by translation of a dominant-negative mutation of the Xenopus FGF receptor in the early embryo, that inhibition of the FGF pathway causes an abnormal phenotype, demonstrating that FGF is involved in important aspects of early embryonic development. The work outlined in this proposal will directly extend these findings and continue recently published studies on the regulation of FGF receptor expression in the early embryo. The overall objective of the proposal is to determine the specific role of FGF in the patterning of the mesoderm.
The specific aims are: 1). To understand the consequences of blocking FGF function in early embryogenesis. Mutant embryos will be studied to determine the range of tissue types generated and whether defects in gene expression are caused by inhibiting the FGF signalling pathway. 2). To determine the level of posttranscriptional control of FGF receptor expression after oocyte maturation and in early embryonic stages. Recently published findings suggest that the regulation of FGF receptor in the early embryo is posttranscriptional. The initial phase will focus on the timing of expression and localization of FGF receptor protein. Possible mechanisms of translational control will be examined. 3). To identify alternate forms of the FGF receptor expressed during embryogenesis. To determine whether the effects of FGF during embryogenesis depend on alternate receptor forms, the search for cDNA clones from early embryonic stage libraries and through a PCR cloning strategy will be undertaken. The function of alternate forms will be tested in an oocyte translation system. Congenital malformations account for significant human morbidity and mortality. The majority of these are from unknown causes. Understanding the early molecular events that direct differentiation pathways and control embryonic development is essential to the full understanding of the pathogenesis of these conditions.
| Doniach, T; Musci, T J (1995) Induction of anteroposterior neural pattern in Xenopus: evidence for a quantitative mechanism. Mech Dev 53:403-13 |
| Robbie, E P; Peterson, M; Amaya, E et al. (1995) Temporal regulation of the Xenopus FGF receptor in development: a translation inhibitory element in the 3' untranslated region. Development 121:1775-85 |
