International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


B Bohnsack
Baylor College of Medicine

Lai L, Niederreither K, Hirschi KK
Baylor College of Medicine

Retinoic acid (RA) plays an integral role in vertebrate development.  Synthesis of RA during early development is regulated via retinaldehyde dehydrogenase-2 (Raldh2)-dependent conversion of dietary retinal to RA.  We examined mice deficient for Raldh2 to determine whether vascular and hematopoietic defects are associated with RA deficiency.  We determined that in Raldh2 -/- mice, endothelial cell differentiation and tube formation occurred, but the initial capillary plexus that formed failed to remodel and recruit mural cells (smooth muscle cells and pericytes) to form a surrounding vessel wall.  Immunostaining further revealed a 1.5-2 fold increase in endothelial cell proliferation in 8.5dpc Raldh2-/- yolk sacs compared to wildtype, and a significant decrease in the expression of cell cycle inhibitors p21 and p27.  Semi-quantitative RT-PCR analysis of RNA isolated from 8.5dpc Raldh2-/- yolk sacs revealed down-regulation of multiple signaling pathways known to be involved in blood vessel assembly, as well as decreased expression of RNA binding protein, quaking, compared to wildtype littermates.  Administration of RA to the pregnant mother from 7.5-8.5dpc, 7.5-9.5dpc or 7.5-12.5dpc progressively decreased endothelial cell proliferation, upregulated key signaling molecules including quaking, and restored vascular structure and branching pattern in the mutants to that observed in wildtype littermates.  In Raldh2-/- yolk sacs, Tal-1 expression was also decreased compared to wildtype littermates, and in vitro hematopoiesis assays revealed defective erythroid and granulopoietic colony formation.  These results suggest that RA signaling is required for normal blood vessel development, and may regulate multiple signaling pathways involved in these processes.

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