Abstract
BackgroundCubilin is a peripheral membrane protein that interacts with the integral membrane proteins megalin and amnionless to mediate ligand endocytosis by absorptive epithelia such as the extraembryonic visceral endoderm (VE).ResultsHere we report the effects of the genetic deletion of cubilin on mouse embryonic development. Cubilin gene deletion is homozygous embryonic lethal with death occurring between 7.5–13.5 days post coitum (dpc). Cubilin-deficient embryos display developmental retardation and do not advance morphologically beyond the gross appearance of wild-type 8–8.5 dpc embryos. While mesodermal structures such as the allantois and the heart are formed in cubilin mutants, other mesoderm-derived tissues are anomalous or absent. Yolk sac blood islands are formed in cubilin mutants but are unusually large, and the yolk sac blood vessels fail to undergo remodeling. Furthermore, somite formation does not occur in cubilin mutants. Morphological abnormalities of endoderm occur in cubilin mutants and include a stratified epithelium in place of the normally simple columnar VE epithelium and a stratified cuboidal epithelium in place of the normally simple squamous epithelium of the definitive endoderm. Cubilin-deficient VE is also functionally defective, unable to mediate uptake of maternally derived high-density lipoprotein (HDL).ConclusionIn summary, cubilin is required for embryonic development and is essential for the formation of somites, definitive endoderm and VE and for the absorptive function of VE including the process of maternal-embryo transport of HDL.
Highlights
Cubilin is a peripheral membrane protein that interacts with the integral membrane proteins megalin and amnionless to mediate ligand endocytosis by absorptive epithelia such as the extraembryonic visceral endoderm (VE)
Cubilin was later shown to be an endocytic receptor for apolipoprotein A-I/high density lipoprotein (HDL), mediating uptake of high-density lipoprotein (HDL) in the kidney and VE [4,5]
A mouse cubilin gene-targeting vector was designed to create a null mutation through deletion of exons 1–6 (Fig. 1)
Summary
Cubilin is a peripheral membrane protein that interacts with the integral membrane proteins megalin and amnionless to mediate ligand endocytosis by absorptive epithelia such as the extraembryonic visceral endoderm (VE). Cubilin is a 460-kDa peripheral membrane protein expressed by a number of absorptive epithelial cells including those of the renal proximal convoluted tubule, ileum and yolk sac extraembryonic visceral endoderm (VE) [1]. Cubilin was later shown to be an endocytic receptor for apolipoprotein A-I (apoA-I)/high density lipoprotein (HDL), mediating uptake of HDL in the kidney and VE [4,5]. Three cell surface integral membrane proteins have been shown to interact with cubilin. The ~48-kDa type I transmembrane protein, amnionless (AMN), is the most recent integral membrane protein found to interact with cubilin [10]. We characterize the consequences of targeted deletion of the mouse cubilin gene on embryonic development
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