Drosophila starvin Encodes a Tissue-Specific BAG-Domain Protein Required for Larval Food Uptake

Abstract

We describe a developmental, genetic, and molecular analysis of the sole Drosophila member of the BAG family of genes, which is implicated in stress response and survival in mammalian cells. We show that the gene, termed starvin (stv), is expressed in a highly tissue-specific manner, accumulating primarily in tendon cells following germ-band retraction and later in somatic muscles and the esophagus during embryonic stage 15. We show that stv expression falls within known tendon and muscle cell transcriptional regulatory cascades, being downstream of stripe, but not of another tendon transcriptional regulator, delilah, and downstream of the muscle regulator, mef-2. We generated a series of stv alleles and, surprisingly, given the muscle and tendon-specific embryonic expression of stv, found that the gross morphology and function of somatic muscles is normal in stv mutants. Nonetheless, stv mutant larvae exhibit a striking and fully penetrant mutant phenotype of failure to grow after hatching and a severely impaired ability to take up food. Our study provides the first report of an essential, developmentally regulated BAG-family gene.

Identification of the Drosophila Ortholog of HSPB8

“…However, we show here that also HSP67Bc colocalizes with ␣-actinin at the Z bands, thus making it difficult to establish functional homology mainly on the basis of subcellular localization. We present here both biochemical and functional evidence that Dm-HSP67Bc, and not CG14207 or L(2)efl, is the closest HSPB8 ortholog; only HSP67Bc interacts with human BAG3, and Dm-Starvin, the sole D. melanogaster BAG protein (34), stimulates autophagy in an eIF2␣-dependent manner and decreases mutated polyglutamine protein aggregation in cells. Furthermore, like human HSPB8, Dm-HSP67Bc protected against mutated polyglutamine-mediated eye degeneration in a SCA3 fly model in vivo.…”

“…HSPB8 acts in a complex with BAG3 (11), a member of the BAG family of proteins (29 -31), and the complex facilitates the clearance of misfolded aggregate-prone proteins (11,32,33). In the current study, we first identified HSP67Bc as a D. melanogaster functional ortholog of human HSPB8, and we show that, like HSPB8, Dm-HSP67Bc interacts with Starvin, the sole BAG D. melanogaster protein (34), and that Dm-HSP67Bc stimulates autophagy. Both human HSPB8 and Dm-HSP67Bc reduce aggregation of ataxin-3 containing an expanded polyglutamine tract and of a mutated form of HSPB1 (P182L-HSPB1) that is associated with peripheral neuropathy.…”

“…Ortholog of Human HSPB8-Whereas the human genome encodes for 10 sHSPs (HSPB1-HSPB10) (14) and for six BAG proteins (BAG1-BAG6) (31), the D. melanogaster genome encodes for 11 small heat shock proteins (small HSPs) (40) and for only one BAG protein, Starvin (34). It has already been shown that knockdown of Starvin results in a severe failure to ingest food and in growth defects, most likely due to impairment of muscle maturation and/or function (34).…”

“…It has already been shown that knockdown of Starvin results in a severe failure to ingest food and in growth defects, most likely due to impairment of muscle maturation and/or function (34). Interestingly, BAG3 knockout mice show a fulminant myopathy and premature death, due to the progressive degeneration of skeletal muscles (41).…”

Waddington's Assimilation, A Fact or A Mere Philosophy Shaped in The Lamarckian Mold: A Genomic Inquiry

“…Vials containing pupae were incubated for 24 hours (at 25°C) and then to specifying vein/intervein cell fates during wing development (for e.g. key targets of the Su(H):NICD complex act as repressors of wing vein formation in the interveins; [20,21] [23]. This inhibition could correlate with the loss of crossveins.…”