Spectrin cytoskeleton defects produce a host of phenotypes affecting the plasma membrane, cell polarity, and secretory membrane traffic. However, many of the underlying molecular mechanisms remain unexplained by prevailing models. Here we used the larval fat body of Drosophila melanogaster as a genetic model system to further elucidate mechanisms of ab-spectrin function. The results provide unexpected new insights into spectrin function as well as mechanisms of dietary fat uptake and storage. We show that loss of a-or b-spectrin in the fat body eliminated a population of small cortical lipid droplets and altered plasma membrane architecture, but did not affect viability of the organism. We present a novel model in which ab-spectrin directly couples lipid uptake at the plasma membrane to lipid droplet growth in the cytoplasm. In contrast, strong overexpression of b-spectrin caused fat body atrophy and larval lethality. Overexpression of b-spectrin also perturbed transport of dietary fat from the midgut to the fat body. This hypermorphic phenotype appears to be the result of blocking secretion of the lipid carrier lipophorin from fat cells. However, this midgut phenotype was never seen with spectrin loss of function, suggesting that spectrin is not normally required for lipophorin secretion or function. The b-spectrin hypermorphic phenotype was ameliorated by co-overexpression of a-spectrin. Based on the overexpression results here, we propose that b-spectrin family members may be prone to hypermorphic effects (including effects on secretion) if their activity is not properly regulated. MEMBERS of the spectrin and ankyrin gene families are ubiquitous in animal cells and defects in these genes are responsible for a range of inherited human disorders, including spinocerebellar ataxia type 5 (SCA5) (Ikeda et al. 2006), anemia (Lux andPalek 1995), and Duchenne muscular dystrophy (Koenig et al. 1988). In most cases, the precise molecular mechanisms underlying the disease process are incompletely understood. Spectrin and ankyrin are most familiar as components of a subplasma membrane protein scaffold known as the spectrin cytoskeleton (Baines 2010). In one long-standing hypothesis the spectrin cytoskeleton is thought to capture and stabilize interacting membrane proteins as they arrive at the cell surface, creating domains of specialized composition and function (Dubreuil 2006).Recent genetic studies in a number of model systems suggest that spectrin and ankyrin have further roles in intracellular membrane traffic (Kizhatil et al. 2007(Kizhatil et al. , 2009Ayalon et al. 2008;Stabach et al. 2008;Clarkson et al. 2010;Lorenzo et al. 2010;Tjota et al. 2011).Given the conservation of spectrin and ankyrin genes between vertebrates and invertebrates, one would expect that their functions should also be conserved. Indeed, as is the case in vertebrates, loss-of-function mutations of a-and b-spectrin and ankyrin2 in Drosophila are lethal early in development (Lee et al. 1993;Dubreuil et al. 2000;Koch et al. 2008;Pielag...
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