Molecular mechanism to regulate the patterning of craniofacial skeleton.

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Expression of the LIM homeodomain transcription factor Lhx8 is restricted to and up-regulated in the mesenchyme of the upper face prominence before lip fusion. Since retinoid is a potential patterning influence on the developing face, we examined the regulation of Lhx8 through retinoic acid(RA) in the maxillary prominence and detected signals that induce or repress Lhx8 expression. Application of exogenous RA caused severe defects of the maxilla. Citral also induced a specific loss of derivatives from the maxillary prominences by blocking RA synthesis. In situ hybridization and RT-PCR analysis of the maxillary mesenchyme revealed that the expression of Lhx8 was significantly down-regulated by RA as well as by Citral and FGF-8b whereas SU5402, a pan-FGF family antagonist, down-regulated the gene and caused defective maxillary morphogenesis and cleft lip. Our data suggest that Lhx8 is regulated by RA signaling through FGF signals during tissue interactions of maxillary morphogenesis.