92-kD gelatinase is commonly expressed in coronary arterial atherosclerotic lesions. Active synthesis of 92-kD gelatinase by macrophages and smooth muscle cells in atherosclerotic lesions may play a pathogenic role in the development of acute coronary ischemia.

qkI, a newly cloned gene lying immediately proximal to the deletion in the quakingviable mutation, is transcribed into three messages of 5, 6, and 7 kb. Antibodies raised to the unique carboxy peptides of the resulting QKI proteins reveal that, in the nervous system, all three QKI proteins are expressed strongly in myelin-forming cells and also in astrocytes. Interestingly, individual isoforms show distinct intracellular distributions: QKI-6 and QKI-7 are localized to perikaryal cytoplasm, whereas QKI-5 invariably is restricted to the nucleus, consistent with the predicted role of QKI as an RNA-binding protein. In quakingviable mutants, which display severe dysmyelination, QKI-6 and QKI-7 are absent exclusively from myelin-forming cells. By contrast, QKI-5 is absent only in oligodendrocytes of severely affected tracts. These observations implicate QKI proteins as regulators of myelination and reveal key insights into the mechanisms of dysmyelination in the quakingviable mutant.

The signal transduction and activation of RNA (STAR) family of RNA-binding proteins, whose members are evolutionarily conserved from yeast to humans, are important for a number of developmental decisions. For example, in the mouse, quaking proteins (QKI-5, QKI-6, and QKI-7) are essential for embryogenesis and myelination , whereas a closely related protein in Caenorhabditis elegans, germline defective-1 (GLD-1), is necessary for germline development. Recently, GLD-1 was found to be a translational repressor that acts through regulatory elements, called TGEs (for tra-2 and GLI elements), present in the 3 untranslated region of the sex-determining gene tra-2. This gene promotes female development, and repression of tra-2 translation by TGEs is necessary for the male cell fates. The finding that GLD-1 inhibits tra-2 translation raises the possibility that other STAR family members act by a similar mechanism to control gene activity. Here we demonstrate, both in vitro and in vivo, that QKI-6 functions in the same manner as GLD-1 and can specifically bind to TGEs to repress translation of reporter constructs containing TGEs. In addition, expression of QKI-6 in C. elegans wild-type hermaphrodites or in hermaphrodites that are partially masculinized by a loss-of-function mutation in the sex-determining gene tra-3 results in masculinization of somatic tissues, consistent with QKI-6 repressing the activity of tra-2. These results strongly suggest that QKI-6 may control gene activity by operating through TGEs to regulate translation. In addition, our data support the hypothesis that other STAR family members may also be TGE-dependent translational regulators.quaking ͉ myelination ͉ mouse ͉ translation control ͉ tra-2 and GLI element (TGE)

Several lines of evidence suggest that platelet-derived growth factor A chain (PDGF-A) is required for normal embryonic cardiovascular development. To test this directly, we introduced anti-PDGF-A neutralizing antibodies into mouse deciduas in utero at Embryonic Days (E) 8.5, 9.5, and 10.5. This resulted in the selective disruption of PDGF-A ligand-receptor interactions in vivo for a period of 18-24 hr and allowed us to assess both if PDGF-A is required for cardiovascular development and when it is required. Embryos collected 48 hr after antibody treatment displayed severe cardiovascular abnormalities. These included both atrial and ventricular myocardial hypertrophy, epicardial and endocardial abnormalities, and aortic dilation, among others. Although heart abnormalities were observed in embryos treated at all three ages, they were more common in embryos treated at E8.5. In contrast, only embryos treated at E10.5 exhibited significant aortic dilation. This work (1) demonstrates directly for the first time that PDGF-A is required for normal cardiovascular development, (2) identifies several processes that require PDGF-A, and (3) defines discreet developmental periods during which these PDGF-A-dependent processes require the factor.