RRC ID 11071
Author Maynard JC, Pham T, Zheng T, Jockheck-Clark A, Rankin HB, Newgard CB, Spana EP, Nicchitta CV.
Title Gp93, the Drosophila GRP94 ortholog, is required for gut epithelial homeostasis and nutrient assimilation-coupled growth control.
Journal Dev. Biol.
Abstract GRP94, the endoplasmic reticulum Hsp90, is a metazoan-restricted chaperone essential for early development in mammals, yet dispensable for mammalian cell viability. This dichotomy suggests that GRP94 is required for the functional expression of secretory and/or membrane proteins that enable the integration of cells into tissues. To explore this hypothesis, we have identified the Drosophila ortholog of GRP94, Gp93, and report that Gp93 is an essential gene in Drosophila. Loss of zygotic Gp93 expression is late larval-lethal and causes prominent defects in the larval midgut, the sole endoderm-derived larval tissue. Gp93 mutant larvae display pronounced defects in the midgut epithelium, with aberrant copper cell structure, markedly reduced gut acidification, atypical septate junction structure, depressed gut motility, and deficits in intestinal nutrient uptake. The metabolic consequences of the loss of Gp93-expression are profound; Gp93 mutant larvae exhibit a starvation-like metabolic phenotype, including suppression of insulin signaling and extensive mobilization of amino acids and triglycerides. The defects in copper cell structure/function accompanying loss of Gp93 expression resemble those reported for mutations in labial, an endodermal homeotic gene required for copper cell specification, and alpha-spectrin, thus suggesting an essential role for Gp93 in the functional expression of secretory/integral membrane protein-encoding lab protein target genes and/or integral membrane protein(s) that interact with the spectrin cytoskeleton to confer epithelial membrane specialization.
Volume 339(2)
Pages 295-306
Published 2010-3-15
DOI 10.1016/j.ydbio.2009.12.023
PII S0012-1606(09)01439-0
PMID 20044986
PMC PMC2830396
MeSH Animals Drosophila / embryology Drosophila / growth & development Drosophila / metabolism* Drosophila Proteins / genetics Drosophila Proteins / metabolism* Embryo, Nonmammalian / metabolism Epithelial Cells / cytology Epithelial Cells / metabolism HSP70 Heat-Shock Proteins / genetics HSP70 Heat-Shock Proteins / metabolism Homeostasis Intestinal Mucosa / metabolism* Larva / metabolism Membrane Proteins / genetics Membrane Proteins / metabolism Molecular Chaperones / genetics Molecular Chaperones / metabolism* Mutation
IF 2.936
Times Cited 24
Drosophila 5520R-1 5520R-3