Effects of retinoic acid excess on expression of Hox-2.9 and Krox-20 and on morphological segmentation in the hindbrain of mouse embryos.

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Abstract
Mouse embryos were exposed to maternally administered RA on day 8.0 or day 7 3/4 of development, i.e. at or just before the differentiation of the cranial neural plate, and before the start of segmentation. On day 9.0, the RA‐treated embryos had a shorter preotic hindbrain than the controls and clear rhombomeric segmentation was absent. These morphological effects were correlated with alterations in the spatiotemporal distribution patterns of two genes, Hox‐2.9 and Krox‐20, which are expressed in the otic and preotic hindbrain and in specific neural crest cell populations. Hox‐2.9 was expressed throughout the preotic hindbrain region, instead of being confined to rhombomere 4. Krox‐20 was not expressed rostral to the Hox‐2.9 domain, i.e. its normal rhombomere 3 domain was absent. The Hox‐2.9/Krox‐20 boundary was ill‐defined, with patches of alternating expression of the two genes. In migrating neural crest cells, Hox‐2.9 expression was both abnormally extensive and abnormally prolonged. Neural crest cells expressing Krox‐20 remained close to the neural tube. Embryos exposed to RA on day 8 1/4 appeared to be morphologically normal. We suggest that early events leading to rhombomeric segmentation and rhombomere‐specific gene expression are specifically vulnerable to raised RA levels, and may require RA levels lower than those in the region of somitic segmentation.