Targeted disruption of cubilin reveals essential developmental roles in the structure and function of endoderm and in somite formation

Brian T. Smith, Jason C. Mussell, Paul A. Fleming, Jeremy L. Barth, Demetri D. Spyropoulos, Marion Anne Cooley, Christopher J. Drake, W. Scott Argraves

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Background: 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). Results: Here 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). Conclusion: In 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.

Original languageEnglish (US)
Article number30
JournalBMC Developmental Biology
Volume6
DOIs
StatePublished - Jun 20 2006

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Somites
Endoderm
Epithelium
Yolk Sac
Embryonic Structures
HDL Lipoproteins
Embryonic Development
Membrane Proteins
Allantois
Low Density Lipoprotein Receptor-Related Protein-2
intrinsic factor-cobalamin receptor
Gene Deletion
Mesoderm
Endocytosis
Blood Vessels
Mothers
Ligands

ASJC Scopus subject areas

  • Developmental Biology

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Targeted disruption of cubilin reveals essential developmental roles in the structure and function of endoderm and in somite formation. / Smith, Brian T.; Mussell, Jason C.; Fleming, Paul A.; Barth, Jeremy L.; Spyropoulos, Demetri D.; Cooley, Marion Anne; Drake, Christopher J.; Argraves, W. Scott.

In: BMC Developmental Biology, Vol. 6, 30, 20.06.2006.

Research output: Contribution to journalArticle

Smith, Brian T. ; Mussell, Jason C. ; Fleming, Paul A. ; Barth, Jeremy L. ; Spyropoulos, Demetri D. ; Cooley, Marion Anne ; Drake, Christopher J. ; Argraves, W. Scott. / Targeted disruption of cubilin reveals essential developmental roles in the structure and function of endoderm and in somite formation. In: BMC Developmental Biology. 2006 ; Vol. 6.
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abstract = "Background: 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). Results: Here 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). Conclusion: In 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.",
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