International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


POSTER 41 - MOLECULAR ROLE OF QUAKING IN BLOOD AND BLOOD VESSEL DEVELOPMENT

KK Hirschi
Baylor College of Medicine

Bohnsack BL, Northrop JL,  Lihua LL,  Justice MJ, Hirschi KK
Baylor College of Medicine

We recently determined that a mutation in the RNA binding domain of quaking yields lethal defects in vascular development.  Analysis of the expression of PE-CAM-1, Tie-2 and SM-a-actin proteins revealed that embryos homozygous for the qkk2 allele exhibit normal endothelial cell commitment and differentiation, but lack endothelial cell maturation and mural cell recruitment, resulting in abnormal vascular remodeling.  Importantly, these mutants exhibit normal cardiac muscle differentiation and cardiac function at this stage of embryonic development.  Thus, these results suggest that quaking plays a primary role in vascular development.  We aimed to elucidate the underlying cellular and molecular role(s) of quaking in blood vessel formation, and investigate whether quaking regulates hematopoietic development.  Our studies revealed down-regulation of multiple signaling pathways known to be involved in blood vessel assembly, including hedgehog, VEGF and TGF-b pathways, as revealed by semi-quantitative RT-PCR of RNA isolated from yolk sacs of qkk2 mutants and wild type littermates.  Furthermore, a decrease in the expression of Tal-1 suggests defects in blood cell commitment and/or differentiation.  Interestingly, the phenotype of the qkk2 mutants parallels that of embryos deficient for retinal-dehydrogenase-2 (Raldh2), which are retinoic acid deficient.  Notably, we have detected a decrease in the expression of Raldh2 in qkk2 mutants.  Thus, the normal functioning of quaking is essential for the maintenance of multiple signaling pathways that are critically important for blood and blood vessel development.  The hierarchy among, and synergy between, these signaling pathways, and how they are regulated by quaking, is under investigation.


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