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

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

doi:10.1186/1471-213x-6-30

Cited by 58 publications

(22 citation statements)

References 35 publications

(44 reference statements)

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“…This situation apparently contrasts with the endoderm of the visceral yolk sac which has a high propensity for DiI-HDL uptake (Hatzopoulos et al, 1998; Smith et al, 2006). Several explanations could account for this disparity.…”

Section: Resultsmentioning

confidence: 99%

“…3B). During embryonic development, a complex of membrane-associated proteins comprising Amnionless (AMN), Cubilin (CUBN) and Megalin (LRP2) is localized to the apical surface of VE cells, where it mediates endocytosis critical for embryogenesis (Kalantry et al, 2001; Smith et al, 2006; Strope et al, 2004; Tomihara-Newberger et al, 1998). We noted that BMP4 treatment increased the level of expression of both Amn (array fold-change (FC)=+16.5) and Lrp2 (array FC=+3.7) in XEN cells.…”

Section: Resultsmentioning

confidence: 99%

“…Uptake can be visualized using a fluorescent DiI-HDL probe (Hatzopoulos et al, 1998; Smith et al, 2006). The status of HDL uptake by PrE cells of the blastocyst or PE is not known.…”

Section: Resultsmentioning

confidence: 99%

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BMP4 signaling directs primitive endoderm-derived XEN cells to an extraembryonic visceral endoderm identity

Artus

Douvaras

Piliszek

et al. 2012

Developmental Biology

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The visceral endoderm (VE) is an epithelial tissue in the early postimplantation mouse embryo that encapsulates the pluripotent epiblast distally and the extraembryonic ectoderm proximally. In addition to facilitating nutrient exchange before the establishment of a circulation, the VE is critical for patterning the epiblast. Since VE is derived from the primitive endoderm (PrE) of the blastocyst, and PrE-derived eXtraembryonic ENdoderm (XEN) cells can be propagated in vitro, XEN cells should provide an important tool for identifying factors that direct VE differentiation. In this study, we demonstrated that BMP4 signalling induces the formation of a polarized epithelium in XEN cells. This morphological transition was reversible, and was associated with the acquisition of a molecular signature comparable to extraembryonic (ex) VE. Resembling exVE which will form the endoderm of the visceral yolk sac, BMP4-treated XEN cells regulated hematopoiesis by stimulating the expansion of primitive erythroid progenitors. We also observed that LIF exerted an antagonistic effect on BMP4-induced XEN cell differentiation, thereby impacting the extrinsic conditions used for the isolation and maintenance of XEN cells in an undifferentiated state. Taken together, our data suggest that XEN cells can be differentiated towards an exVE identity upon BMP4 stimulation, and therefore represent a valuable tool for investigating PrE lineage differentiation.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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BMP4 signaling directs primitive endoderm-derived XEN cells to an extraembryonic visceral endoderm identity

Artus

Douvaras

Piliszek

et al. 2012

Developmental Biology

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“…Gata3 was selected for its role during cardiomyocyte differentiation and early steps of heart tube morphogenesis (Cripps and Olson, 2002), and Glutathione-S-Transferase (GstP) for its importance in detoxification pathways. We selected the receptor Cubilin (gp280) (Sahali et al, 1988; Smith et al, 2006) and Sumo1, encoding for a protein that mediates sumoylation of histones and transcription factors, for their role in regulation of transcription during embryogenesis (Alkuraya et al, 2006). …”

Section: Resultsmentioning

confidence: 99%

Gene expression profiling in the fetal cardiac tissue after folate and low‐dose trichloroethylene exposure

Caldwell

Manziello

Howard

et al. 2009

Birth Defects Research

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Background Previous studies show gene expression alterations in rat embryo hearts and cell lines that correspond to the cardio-teratogenic effects of trichloroethylene (TCE) in animal models. One potential mechanism of TCE teratogenicity may be through altered regulation of calcium homeostatic genes with a corresponding inhibition of cardiac function. It has been suggested that TCE may interfere with the folic acid/methylation pathway in liver and kidney and alter gene regulation by epigenetic mechanisms. According to this hypothesis, folate supplementation in the maternal diet should counteract TCE effects on gene expression in the embryonic heart. Approach To identify transcriptional targets altered in the embryonic heart after exposure to TCE, and possible protective effects of folate, we used DNA microarray technology to profile gene expression in embryonic mouse hearts with maternal TCE exposure and dietary changes in maternal folate. Results Exposure to low doses of TCE (10ppb) caused extensive alterations in transcripts encoding proteins involved in transport, ion channel, transcription, differentiation, cytoskeleton, cell cycle and apoptosis. Exogenous folate did not offset the effects of TCE exposure on normal gene expression and both high and low levels of folate produced additional significant changes in gene expression. Conclusions A mechanism where TCE induces a folate deficiency does not explain altered gene expression patterns in the embryonic mouse heart. The data further suggest that use of folate supplementation, in the presence of this toxin, may be detrimental and non-protective of the developing embryo.

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“…The availability of a mouse carrying a knockin of an EGFP cassette into the cubilin gene [17] has enabled precise histological analysis of cubilin expression. While evaluating cubilin-EGFP expression in renal tissue of mice heterozygous for the knockin allele, we observed a striking difference in the distribution of EGFP immunoreactivity versus cubilin immunoreactivity.…”

Section: Introductionmentioning

confidence: 99%

Cubilin expression is monoallelic and epigenetically augmented via PPARs

et al. 2013

Self Cite

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BackgroundCubilin is an endocytic receptor that is necessary for renal and intestinal absorption of a range of ligands. Endocytosis mediated by cubilin and its co-receptor megalin is the principal mechanism for proximal tubule reabsorption of proteins from the glomerular filtrate. Cubilin is also required for intestinal endocytosis of intrinsic factor-vitamin B12 complex. Despite its importance, little is known about the regulation of cubilin expression.ResultsHere we show that cubilin expression is under epigenetic regulation by at least two processes. The first process involves inactivation of expression of one of the cubilin alleles. This monoallelic expression state could not be transformed to biallelic by inhibiting DNA methylation or histone deacetylation. The second process involves transcriptional regulation of cubilin by peroxisome proliferator-activated receptor (PPAR) transcription factors that are themselves regulated by DNA methylation and histone deacetylation. This is supported by findings that inhibitors of DNA methylation and histone deacetylation, 5Aza and TSA, increase cubilin mRNA and protein in renal and intestinal cell lines. Not only was the expression of PPARα and γ inducible by 5Aza and TSA, but the positive effects of TSA and 5Aza on cubilin expression were also dependent on both increased PPAR transcription and activation. Additionally, 5Aza and TSA had similar effects on the expression of the cubilin co-receptor, megalin.ConclusionsTogether, these findings reveal that cubilin and megalin mRNA expression is under epigenetic control and thus point to new avenues for overcoming pathological suppression of these genes through targeting of epigenetic regulatory processes.

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

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).

Cited by 58 publications

References 35 publications

BMP4 signaling directs primitive endoderm-derived XEN cells to an extraembryonic visceral endoderm identity

BMP4 signaling directs primitive endoderm-derived XEN cells to an extraembryonic visceral endoderm identity

Gene expression profiling in the fetal cardiac tissue after folate and low‐dose trichloroethylene exposure

Cubilin expression is monoallelic and epigenetically augmented via PPARs

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