FGF AND BMP IN NEURAL TUBE DEVELOPMENT

Duke University, Durham NC

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Abstract

Description (Provided by applicant): Neural tube defects (NTDs) occur in 1:1000 pregnancies and can be lethal or result in significant morbidity over the lifetime of a surviving affected child. While significant effort has been made in this area, the etiology of human NTDs still remains largely unknown. The applicant proposes to study the developmental basis of NTDs utilizing murine models. Preliminary data from a transgenic mouse line the applicant has generated indicates that Fgf signaling may play a role in neural tube closure and therefore NTDs. This transgenic line ectopically expresses Fgf4 in the developing neural plate and results in a severe NTD. In addition, preliminary loss of function studies of both Fgf and Bmp inhibitory signals indicate that a balance between the Bmp and Fgf signaling families is required for normal neural tube patterning and closure. The specific aims of this proposal are designed to examine the role of Fgf signaling in neural tube formation with emphasis on the interaction between Fgfs and Bmps in dorsal neural development. Utilizing Cre/LoxP transgenic technology, two specific aims are to perform tissue specific overexpression and inhibition of Fgf signaling in the developing neural plate. Two conditional transgenic lines will be generated, one that ectopically expresses Fgf and another that express a dominant negative Fgf receptor. Expression of either of these transgenes will be dependent upon Cre recombination. By crossing these lines to a third existing transgenic line that expresses Cre in the developing neural folds, embryos will be generated that have either gain or loss of Fgf function specifically in the developing neural tissue at the time of neural tube closure. The investigators will then examine the effect of these genetic manipulations on the development and patterning of the neural tube and neural crest with emphasis on Bmp signaling changes. The third specific aim is an analysis of embryos with targeted genetic defects of both Fgf8 and Bmp signaling genes to determine the nature of the neural tube patterning defects that occur in these embryos. Such aspects as neural cell specification, proliferation and dorsal ventral patterning of the forming neural tube will be examined.