SPARC as an essential regulator of fat body development and maintenance critical for Drosophila melanogaster larval progression

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The emergence of multicellular organisms was co-incident with the appearance of genes coding for extracellular matrix (ECM) molecules that gave rise to two distinct ECMs, interstitial matrices and basal laminae (BL)/basement membranes. BL, which are highly conserved in multicellular organisms, underlie epithelial and endothelial cells and envelop tissues and organs as well as nerves, muscle fibers and adipocytes. In addition to providing mechanical support and serving as an adhesive substrata for cell migration and survival, BL make critical contributions to the development of organisms via interactions with a diverse number of transmembrane receptors, growth factors and cytokines. The basic components of BLs include network-forming Collagen IV (ColIV), Laminin (LM), Perlecan, and Nidogen, which are assembled into sheet-like networks through complex and still poorly understood processes. The goal of the research program outlined in this application is to define key components that orchestrate BL assembly using Drosophila melanogaster as a model. We have shown that SPARC (Secreted Protein, Acidic, Rich in Cysteine), a Ca2+- and collagen-binding matricellular diffusible glycoprotein, is a major component of Drosophila embryonic BL. Our recent data indicate that SPARC deficiency leads to larval lethality associated with precocious remodelling of fat body BL. The embryonic and larval fat body is essential to fly development that functions nutrient storage and regulation of energy availability. The fat body is largely composed of adipocytes, individually enveloped within a BL, similar to adipocytes within vertebrates. Loss of SPARC results in rounded fat body adipocytes surrounded with an accumulation of improperly assembly BL components and precocious feeding behavior. Clonal analyses revealed that the accumulation of BL components was cell autonomous. Larval lethality was rescued with a genomic construct expressing SPARC under the control of the native SPARC promoter and driver lines restricting SPARC expression to the fat body. Based on these findings, we hypothesize that SPARC, via Ca2+-dependent interactions with CoIIV, promotes the proper sheet-like assembly of BL surrounding adipocytes. Loss of SPARC results in the aberrant formation and accumulation of BL, leading to remodeling of the fat body that results in larval lethality.