Abstract
The visceral endoderm is a polarized epithelial monolayer necessary for early embryonic development in rodents. A key feature of this epithelium is an active endocytosis and degradation of maternal nutrients, in addition to being the source of various signaling molecules or inhibitors required for the differentiation and patterning of adjacent embryonic tissues. Endocytosis across the visceral endoderm epithelium involves specific cell surface receptors and an extensive sub-membrane vesicular system with numerous apical vacuoles/lysosomes. We previously reported that Cubilin, the endocytic receptor for intrinsic factor-vitamin B12, albumin and apolipoproteinA-I/HDL allows maternal nutrient uptake by the visceral endoderm. In the present study, we show that the germline ablation of Cubilin impairs endodermal and mesodermal patterning, and results in developmental arrest at gastrulation. Notably, visceral endoderm dispersal is impeded in Cubilin null embryos. We further confirm the essential role of Cubilin in nutrient internalization by the early visceral endoderm and highlight its involvement in the formation of apical vacuoles. Our results reveal essential roles for Cubilin in early embryonic development, and suggest that in addition to its nutritive function, Cubilin sustains signaling pathways involved in embryonic differentiation and patterning.
Highlights
Three and a half days after fertilization (E3.5) the mouse blastocyst consists of an outside layer of polarized trophectodermal cells and a cluster of inner cells, the inner cell mass (ICM)
At this stage Cubn mRNA is abundantly expressed in the primitive endoderm (PrE) and Cubilin immunostaining is clearly associated with the apical plasma membrane reflecting the polarization of PrE cells (Fig. 1C,D)
We show that Cubilin is an early pan-visceral endoderm (VE) marker involved in emVE dispersal, as well as the formation of the VE endocytic apparatus
Summary
Three and a half days after fertilization (E3.5) the mouse blastocyst consists of an outside layer of polarized trophectodermal cells and a cluster of inner cells, the inner cell mass (ICM). Cubilin (Cubn, ~460 kDa) is a multiligand receptor predominantly expressed in the embryonic and adult gut and kidney, as well as in the VYS11. Cubilin consists of an N-terminal stretch followed by 8 epidermal growth-factor (EGF) like repeats and 27 CUB (Complement C1r/C1s, Uegf, BMP1) domains involved in ligand binding. It is a peripheral membrane protein with no transmembrane domain or GPI anchor. In the gut it is critical for the physiological uptake of vitamin B12 complexed with its carrier, the gastric intrinsic factor. In the VYS, Cubilin is essential for maternal lipid and protein uptake and inhibition of its function impairs normal embryonic growth[18,19,20,21]. Missense variants in CUBN were associated with nephrotic syndrome and albuminuria, colorectal cancer progression and a risk of neural tube defects[26,27,28]
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