New molecular concepts on pattern formation in limb morphogenesis.

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In terms of the anterior-posterior axis formation in a developing limb bud, a gene, mario, which has unique expression pattern in the limb bud, has a crucial role in the antero-posterior patterning, and a part of the molecular cascade for the patterning, including mario and bmp, was identified. Also, digit number in Xenopus forelimb is identified as not 1234 but 2345 by expression analysis of HoxD genes.In terms of the proximal-distal axis formation in the limb bud, a detailed fate map showed that future autopod region and future zeugopod region is largely overlapped in an early limb bud, but that the overlap is getting smaller as the development proceeds. Hoxa13/Hoxall expression profile confirmed these results from the fate map. Also, the expression analysis revealed that the molecular condition in the distal limb bud is changing progressively.A series of transplantation experiments suggested that a factor(s) from the axial structure, somites determines limb-type identity. Transplantation of different level of somites induced transition of Tbx4/5 expression and inhibited outgrowth of the hindlimb bud. These results suggest that positioning of limb field and its identity are specified not in an autonomous manner in the lateral plate mesoderm but that the tissue-tissue interactions are important.Epigenetic regulation of shh expression was examined, and the results indicated a well correlation between shh expression and DNA methylation of shh enhancer sequence (shh-expressing tissues had low condition of DNA methylation in the enhancer region), suggesting that epigenetic control of shh enhancer region plays a role in shh expression during limb development and regeneration.