Molecular mechanism that controls early morphogenesis of the vertebrate respiratory system

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(1) The expression domain of Fgf10 become restricted the mesoderm lining the endodermal protruding of the primary bronchus. This restriction takes place at the anterior expression boundary of graded Hoxb-6 expression domain. From gain-and loss-of-function experiment, we found that ectopic Fgf10 expression was induced at both side of the Hoxb-6 expression boundary. This indicates that Fgf10 expression is induced by Hoxb-6 dependent cell to tell communication. Actuary we found that Hoxb-6 represses EphA4 expression and activates efnb1 expression. Ectopic EphA4 or efnb1 expression induces Fgf10 expression at their expression boundary, indicating that these molecules are involved in the Fgf10 expression. In addition, we found that the expression boundary of Hoxb-6 has a role of the signaling center and induces the paired morphogenesis of the primary bronchus at the posterior region of the respiratory anlagen. (2) We tried to identify the lung specific enhancer of Fgf10 gene by transgenic mouse system. We found that the multiple lung specific enhancers are present in the introngenic 7kb DNA that also carries the limb bud specific enhancer. The lung specific enhancers cooperate each other with the sequence present in the Fgf10 promoter and/or 5' upstream sequence for lung specific expression. (3) We tried to identify the genes that are specifically expressed in the lung anlagen by microarray analysis followed by WISH. We found that transcription factors potentially involved in the control of Fgf10, for example Isl1 and Tbx20, are identified as a candidate gene. Interestingly, majority of these genes are also expressed in the heart, indicating that similar mechanism is present for induction both heart and lung anlagen at early development. Wnt2 expression was found from very early in the lung anlagen, indicating the involvement of Fgf10 expression through Wnt/beta-catenin system.