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BOR - Papers in Press, published online ahead of print December 22, 2004.
Biol Reprod 2004, 10.1095/biolreprod.104.036913
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BIOLOGY OF REPRODUCTION 72, 1079–1086 (2005)
DOI: 10.1095/biolreprod.104.036913
© 2005 by the Society for the Study of Reproduction, Inc.

Expression and Role of Cubilin in the Internalization of Nutrients During the Peri-Implantation Development of the Rodent Embryo1

Emeline Assémat 3 4, Stéphanie Vinot 3 5, Françoise Gofflot 6, Patrick Linsel-Nitschke 7, Françoise Illien 4, François Châtelet 4, Pierre Verroust 4, Sophie Louvet-Vallée 5, Franz Rinninger 7, and Renata Kozyraki 2 4

Inserm,4 UMR 538, Faculté de Médecine Saint-Antoine, Laboratoire de Biologie Cellulaire du Développement,5 CNRS, UMR7622, Université Pierre et Marie Curie, 75012 Paris, France Unit of Developmental Genetics,6 Université Catholique de Louvain, B-1200 Brussels, Belgium Department for Internal Medicine,7 Universitaetsklinikum Hamburg-Eppendorf, D-20246 Hamburg, Germany

Histiotrophic nutrition is essential during the peri-implantation development in rodents, but little is known about receptors involved in protein and lipid endocytosis derived from the endometrium and the uterine glands. Previous studies suggested that cubilin, a multiligand receptor for vitamin, iron, and protein uptake in the adult, might be important in this process, but the onset of its expression and function is not known. In this study, we analyzed the expression of cubilin in the pre- and early post-implantation rodent embryo and tested its potential function in protein and cholesterol uptake. Using morphological and Western blot analysis, we showed that cubilin first appeared at the eight-cell stage. It was expressed by the maternal-fetal interfaces, trophectoderm and visceral endoderm, but also by the future neuroepithelial cells and the developing neural tube. At all these sites, cubilin was localized at the apical pole of the cells exposed to the maternal environment or to the amniotic and neural tube cavities, and had a very similar distribution to megalin, a member of the LDLR gene family and a coreceptor for cubilin in adult tissues. To analyze cubilin function, we followed endocytosis of apolipoprotein A–I and HDL cholesterol, nutrients normally present in the uterine glands and essential for embryonic growth. We showed that internalization of both ligands was cubilin dependent during the early rodent gestation. In conclusion, the early cubilin expression and its function in protein and cholesterol uptake suggest an important role for cubilin in the development of the peri-implantation embryo.

cholesterol, cubilin, endocytosis, megalin, peri-implantation development


1 Supported by grants from the Fondation pour la Recherche Médicale (F.R.M.), the Association pour la Recherche sur le Cancer (no. 3443), the ACI Biologie du Développement et Physiologie Intégrative (1A068G), the EEC (QLG1-CT-2002-01215), and the La Ligue contre le Cancer. E.A. and S.V. are recipients of a fellowship from the Ministère Français de la Recherche.

2 Correspondence: Renata Kozyraki, INSERM UMR 538, 27 rue de Chaligny, 75012 Paris, France. FAX: 33 1 400 11 390; renata.kozyraki{at}chusa.jussieu.fr

3 E.A. and S.V. participated equally in the work




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