No abstract

Marfan syndrome (MFS), a relatively common autosomal dominant hereditary disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular systems, is caused by mutations in the gene for fibrillin-1 (FBN1). The leading cause of premature death in untreated individuals with MFS is acute aortic dissection, which often follows a period of progressive dilatation of the ascending aorta. Recent research on the molecular physiology of fibrillin and the pathophysiology of MFS and related disorders has changed our understanding of this disorder by demonstrating changes in growth factor signalling and in matrix-cell interactions. The purpose of this review is to provide a comprehensive overview of recent advances in the molecular biology of fibrillin and fibrillin-rich microfibrils. Mutations in FBN1 and other genes found in MFS and related disorders will be discussed, and novel concepts concerning the complex and multiple mechanisms of the pathogenesis of MFS will be explained.

. 11. Complementary DNAs encoding the short forms of G␣ s WT and G␣ s * (9) were subcloned into pUAST (7) and used to transform flies [A. Spradling, in Drosophila: A Practical Approach, D. Roberts, Ed. (IRL Press, Oxford, 1986), pp. 75 -197]. The UAS-G␣ s lines were verified by Msc I digestion of polymerase chain reaction-amplified G␣ s transgenes to detect the presence of a site found in G␣ s WT but lacking as a result of the Q215L mutation. 12. 238Y and 201Y are described in (17) and C232 in (18). C747 shows identical expression to that of C772 (17) (24). C309 is described by J. D. Armstrong [thesis, University of Glasgow, Scotland (1995)]. The O'Kane laboratory screened 500 P-GAL4 lines to identify OK66, OK86, OK62, OK107, OK348, and OK415. 13. T. Tully and W. Quinn, J. Comp. Physiol. 157, 263 (1985); T. Tully, T. Preat, S. Boynton, M. Del Vecchio, Cell 79, 35 (1994). 14. In total, we analyzed behaviorally 16 P-GAL4 insertions that expressed to some degree in MBs. Flies with four insertions (OK66, OK86, KL65, and KL107) showed reduced learning in the absence of expression of constitutively activated G␣ s *, most likely because of genetic background differences. These were not tested further. Flies with eight insertions showed defects in olfactory acuity (30Y, C35, OK62, OK107, C302, OK415, and C532) or shock reactivity (C772), as transheterozygotes with UAS-G␣ s *. These were eliminated from further behavioral testing. Flies with the remaining four P-GAL4 insertions (201Y, 238Y, C309, and C747) showed disrupted learning but normal olfactory acuity and shock reactivity, as transheterozygotes with at least one UAS-G␣ s * insertion. We characterized a total of two P-GAL4 insertions (C232 and OK348) that expressed to some degree in the CC. 15. We suggest that olfactory learning results from G sdependent convergence of the conditional stimulus (CS) and unconditional stimulus (US) in the MBs. This belief is reinforced by the observation that expression of G␣ s * in the CC does not affect learning.