Distinct functions of the major Fgf8 spliceform, Fgf8b, before and during mouse gastrulation

Development. 2007 Jun;134(12):2251-60

Guo Q, Li JY.

The vertebrate gene produces multiple protein isoforms by alternative splicing. Two evolutionarily conserved spliceforms, and , exhibit distinct bioactivities, with Fgf8b having a more potent inductive activity due to higher affinity for Fgf receptors. To investigate the in vivo requirement for Fgf8b, we created a splice-site mutation abolishing Fgf8b expression in mice. Analysis of this mutant has uncovered a novel function of Fgf8 signaling before the onset of gastrulation. We show that the loss of Fgf8b disrupts the induction of the brachyury gene in the pregastrular embryo and, in addition, disrupts the proper alignment of the with the shape of the embryo and the uterine axes at embryonic day (E) 6.5. Importantly, Fgf8-null embryos display the same phenotype as Fgf8b-deficient embryos at E6.5, demonstrating that signaling by Fgf8b is specifically required for development of the . By contrast, during , Fgf8a can partially compensate for the loss of Fgf8b in . We show that an increased level of Fgf8a expression, which leads to Fgf4 expression in the primitive streak, can also promote mesoderm migration in the absence of Fgf8b. Therefore, different Fgf signals may have distinct requirements for the morphogenesis and gene regulation before and during gastrulation. Importantly, our findings implicate Fgf8 in the morphogenetic process that establishes the defined relationship between the axes of the embryo and the uterus at the beginning of gastrulation, a perplexing phenomenon discovered two decades ago.

DISCUSSION Fgf8bis the major splice variant of the Fgf8gene, and Fgf8b proteins have more potent activity than Fgf8a. In this study, by knocking out Fgf8bin the mouse embryo, we have uncovered distinct requirements for Fgf8bbefore and during gastrulation. We show that before the onset of gastrulation,Fgf8bis essential for Fgf8 activities in the induction ofTand positioning the AP axis relative to the shape of the embryo and the uterine axis. Moreover, Fgf8bis required for the normal induction of Lefty2in the emerging streak. During gastrulation, Fgf8acan partially compensate for the loss of Fgf8b.Our molecular and genetic studies suggest that a higher level of Fgf8a is required for promoting mesoderm migration than that for mesoderm specification.

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Fgf8 is essential for embryo remodeling before gastrulation

The uterus influences positioning of pregastrular embryos according to the shape but not the AP axis of the embryo

Fgf8b is involved in the initiation of T expression

Different levels of Fgf8a expression govern mesoderm specification and migration

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