| Anterior-posterior axis determination and elongation is a critical event during early embryonic development. Although studies of human birth defects that affect axis determination and mouse genetic studies have advanced our understanding of signaling pathways involved in anterior-posterior patterning, the relationship between embryonic patterning and its energy requirement has not been investigated.;Here I describe an ENU-induced mutation, nearly headless (nehe), which disrupts normal forebrain development. nehe is a hypomorphic allele of the gene encoding Lipoic acid Synthetase (Lias), which catalyzes the synthesis of lipoic acid, an essential cofactor for several multienzyme complexes required for oxidative metabolism. Forebrain development is compromised from headfold stage in nehe mutants, without a concomitant increase in apoptosis at that stage. Cell proliferation is globally reduced in nehe mutants at a time window from headfold stage to early-somite stage, which explains the 12-hour delay seen in the development of mutant embryos after the early-somite stage. Three groups of cells, the anterior visceral endoderm, the anterior definitive endoderm and the anterior axial mesendoderm (prechordal plate) have been shown to be important for anterior neural patterning. Although the anterior visceral endoderm and the anterior definitive endoderm, which are required for normal anterior neural specification, are able to form normally in nehe mutants, specification and cell morphology of the prechordal plate was abnormal. I also show that the level of phosphorylated (active) AMPK, a cellular energy sensor which affects cell polarity, is up-regulated in nehe mutants. These results suggest that the nehe phenotype arises because normal energy production is required for the specialized morphogenetic movements that generate the prechordal plate, which promotes normal forebrain development in embryos.;Anterior-posterior axis elongation also depends on the addition of cells from the tail bud to the caudal end of the embryo and normal morphogenetic movements such as convergent extension. Here I show that short tail mutant embryos, carrying mutation in the gene encoding receptor tyrosine like orphan receptor 2 (Ror2), fail to elongate the anterior-posterior axis. Ror2 has been implicated in convergent extension in other vertebrates. The short tail mutant defines aspects of a novel signaling pathway involved in anterior-posterior elongation. |
