1 Molecular Biology Graduate Program, Weill Graduate School of Medical Sciences
of Cornell University, New York, NY 10021, USA
2 Developmental Biology Program, Sloan-Kettering Institute for Cancer Research,
1275 York Avenue, New York, NY 10021, USA
* Author for correspondence (e-mail: e-lacy{at}mskmail.mskcc.org)
Accepted 7 July 2004
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SUMMARY |
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Key words: Amnionless, Visceral endoderm, Kidney proximal tubules, Cubilin, Gastrulation
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Introduction |
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Amn encodes a novel predicted type I transmembrane protein of 458
amino acids (Kalantry et al.,
2001). The only homology domain identified by sequence analysis is
a stretch of 70 amino acids, displaying similarity to cysteine-rich (CR)
regions present in a small group of proteins known to function as BMP
inhibitors: chordin, short gastrulation and procollagen IIA
(Kalantry et al., 2001
).
During gastrulation, Amn is expressed exclusively on the apical surface of the
VE facing the maternal environment
(Kalantry et al., 2001
). As
the primary morphological defects of amn reside in epiblast
derivatives, Amn acts cell non-autonomously in the VE to support epiblast cell
behaviors required for assembly of a functional middle streak and growth of
the embryo. It is unknown how Amn mediates these events and whether its
function requires the CR region; however, its apical localization on the VE
supports the hypothesis that Amn transports signaling molecules and/or
nutritive factors from the maternal environment to the underlying
epiblast.
We report here that mouse Amn is also expressed in kidney proximal tubules
(KPT) and small intestine, two resorptive epithelia that morphologically
resemble the VE. Our analysis of Amn-/- embryonic stem
cell (ESC)ROSA26+/+ blastocyst (Amn-/-
+/+)
chimeras reveals that Amn is not required for proliferation or differentiation
in these tissues. However, Amn is required for proper kidney function as adult
chimeric animals exhibit variable proteinuria.
While our analyses of Amn-/-+/+ chimeras were in
progress, Tanner et al. documented mutations in human AMN in five
families with recessive hereditary megaloblastic anemia (MGA1, OMIM#261100;
also known as Imerslund-Gräsbeck disease)
(Tanner et al., 2003
). MGA1,
which is characterized by abnormally large erythroid precursors/erythrocytes
and impaired DNA synthesis, results from a deficiency in vitamin B12
(Broch et al., 1984
).
Previously, 17 families with MGA1 were identified with mutations in cubilin
(CUBN), which encodes the intrinsic factor (IF)-vitamin B12 receptor
in the small intestine (Aminoff et al.,
1999
). CUBN, a 460 kDa glycoprotein, binds to numerous ligands,
including IF-vitamin B12, apolipoprotein A1 (Apoa1), high density lipoprotein
(HDL), transferrin and albumin (Muller et
al., 2003
). As CUBN lacks a transmembrane domain, it has been
proposed that megalin, a low-density lipoprotein receptor family member,
stabilizes CUBN at the cell surface and mediates endocytosis of CUBN-bound
ligands (Hammad et al., 2000
;
Moestrup et al., 1998
). The
association of both AMN and CUBN mutations with MGA1 argues
that AMN, like CUBN, is required for vitamin B12 absorption and suggests that
AMN function is intimately linked with CUBN function and possibly also
megalin.
Exploring the relationship between Amn and Cubn, we have determined that
Cubn is not appropriately localized to the apical cell surface of
Amn-deficient VE and KPT. In addition, adult
Amn-/-+/+ chimeras excrete increased levels of the
Cubn ligands albumin and transferrin in the urine. These data indicate that
Amn is required for proper localization and function of Cubn in vivo. In
addition, they support a model in which endocytosis/transcytosis by Amn/Cubn
on the VE provides a factor(s) to the epiblast essential for primitive streak
assembly and function during gastrulation. The amn mutant phenotype
highlights the role of extra-embryonic tissues in the coordination of growth
and patterning in the gastrulation-stage mouse embryo. While Amn is required
for murine gastrulation, it is apparently not essential for human gastrulation
(Tanner et al., 2003
), a
finding that probably reflects distinct anatomical differences in the
organization of extra-embryonic tissues relative to the epiblast, as well as
different mechanisms for nutrient and waste exchange between mouse and human
embryos.
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Materials and methods |
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Generation of Amn-/-+/+ blastocyst chimeras
ESC were derived from blastocysts generated by intercrosses of 129/Sv
Amnamn/+ mice or 129/B6 Amngfp/+ mice,
as described (Nagy et al.,
2003). From 200 blastocysts, 39 ESC lines were established and
genotyped by PCR as previously described
(Kalantry et al., 2001
;
Wang et al., 1996
). We
identified two Amn mutant ESC lines, line 9
(Amnamn/amn) and line 2-41
(Amngfp/gfp), which are interchangeably designated as
Amn-/- ESC. Blastocysts from B6xB6/129 ROSA26
crosses were injected with Amn-/- ESC or
Amn+/- ESC, surgically transferred into the uteri of
pseudopregnant foster mothers, and allowed to develop to E16.5 or to term.
Wild-type cells were distinguished by ß-galactosidase activity as
described (Nagy et al., 2003
).
For live-born chimeras, contribution of Amn-/- cells was
estimated by X-gal staining of tail tips. In adult chimeric tissues,
Amn-deficient tissues were identified by the absence of Amn antibody
staining.
Urinalysis and Western blotting analysis
Overnight collection of urine samples from adult chimeras was performed in
metabolic cages (Lab Products). In the urine samples, creatinine and albumin
were measured respectively by the Creatinine Companion kit and the Albuwell M
kit (Exocell). Transferrin was measured by the Mouse Serum Transferrin kit
(Alpha Diagnostic) with modifications suggested by the company for urine
samples. For western blotting analysis, loading volumes were normalized by
creatinine values. They were equivalent to 163 ng creatinine (albumin) or 2.45
µg creatinine (transferrin and lysozyme).
Western blotting analysis was performed according to standard protocols using ECL Plus Western blotting detection reagents (Amersham Biosciences). Antibody dilutions used were goat anti-mouse albumin (Bethyl Laboratories) at 1:10,000, rabbit anti-human transferrin (Dako) at 1:1000 and rabbit anti-human lysozyme (Dako) at 1:1000.
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Results |
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If Amn is required for cell proliferation in kidney and intestine,
Amn-/- cells will be underrepresented when compared to +/+
cells in these fetal chimeric tissues. As shown in
Fig. 3,
Amn-/- cells (red arrows) efficiently contribute to both
fetal kidney tubules (Fig. 3A)
and intestinal epithelium (Fig.
3B). Furthermore, we observed from zero to nearly 100%
contribution of Amn-/- cells in both Amn-expressing
(kidney and intestine) and non-expressing (liver) tissues in individual
animals. Similar results were obtained in control
Amn+/-+/+ chimeras (data not shown). Thus, Amn is
not required for cell proliferation in these tissues during fetal
development.
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To assess whether Amn functions in cell differentiation, we examined the
lectin-staining profile of Amn-deficient KPT. Amn-deficient kidneys were
stained with LTL, which specifically recognizes KPT
(D'Agati and Trudel, 1992). As
shown in Fig. 3F, the complete
absence of X-gal staining identified tubules composed of 100%
Amn-/- cells; such tubules labeled robustly with LTL
(Fig. 3E). Therefore, Amn is
not required cell-autonomously for differentiation of KPT cells or cell
non-autonomously for the development of any other component of the
nephron.
Cubilin is not properly localized to the apical cell surface of Amn-deficient cells
The finding that mutations in either CUBN or AMN
independently cause human MGA1 argues that the two proteins act in the same
endocytic pathway. A canine model for MGA1 provides a further clue to the
nature of this interaction. While affected dogs do not bear mutations in
Cubn, Cubn itself is mislocalized, suggesting that another protein is
required to insert Cubn on the apical membrane
(Fyfe et al., 1991a;
Fyfe et al., 1991b
). As shown
in Fig. 4A-C, Amn, Cubn and
megalin co-localize to the apical surface of the VE in E7.5 wild-type mouse
embryos. Such co-localization supports a possible functional relationship
among Amn, Cubn and megalin in the mouse. In amn, megalin is
appropriately localized to the apical surface of the VE
(Fig. 4D,d). Furthermore,
antibody staining indicates that Amn-deficient VE takes up lysozyme, a
megalin-specific ligand (Orlando et al.,
1998
), revealing that megalin is functionally intact (insets in
Fig. 4a,d). By contrast, Cubn
fails to localize to the apical surface of the VE in amn
(Fig. 4F,f). Additionally, as
mislocalization of Cubn is observed at E6.5 prior to the morphological
appearance of the amn phenotype, it is not a secondary consequence of
the amn phenotype (data not shown). Interestingly, Cubn is
mislocalized, despite proper megalin expression and function on Amn-deficient
VE. Thus, contrary to previously proposed models, megalin is not sufficient
while Amn is essential for Cubn localization in the VE.
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Discussion |
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As predicted by their proposed interdependent function, Amn and Cubn are
co-expressed in small intestine and in KPT in mouse, human and dog, as well as
in the mouse VE. AMN and CUBN are both required in humans, and most probably
dogs, for IF-vitamin B12 absorption by the intestine. Amn-deficient
intestine in the mouse appears to develop properly and analysis of blood
samples of high contribution chimeras did not show evidence of megaloblastic
anemia (data not shown). Indeed, as adult Amn-/-+/+
chimeras in this study were mosaics of Amn-/- and +/+
cells, a small number of Amn-expressing intestinal cells may supply the animal
with sufficient supplies of vitamin B12. Conditional knockout strategies are
in progress to assess whether mice with Amn-deficient intestines display
symptoms of megaloblastic anemia.
Proteinuria, which is often associated with MGA1, probably reflects a
deficiency in an endocytic function of AMN/CUBN within KPT. Likewise, dogs
with mislocalized Cubn excrete approximately seven times more albumin in urine
than do wild-type controls (Birn et al.,
2000). The Amn-/-
+/+ chimeras described
in this study also present with defects in KPT function. In particular,
selective proteinuria is observed for Cubn-bound ligands, such as albumin and
transferrin. However, megalin-bound ligands appear unaffected, pointing to
Amn/Cubn-specific, megalin-independent, endocytic functions in the KPT. In
agreement with Amn/Cubn acting as a separate endocytic receptor complex, Fyfe
et al. have found that following transfection of AMN and CUBN
expression vectors, CHO cells were able to endocytose IF-vitamin B12
(Fyfe et al., 2004
).
Potential ligands for the Amn/Cubn complex in the mouse gastrula
Although the crucial ligand for AMN/CUBN in the intestine is IF-vitamin
B12, the crucial ligand during murine gastrulation has not been identified.
IF-vitamin B12 is not a likely candidate, as it is found only in the
stomach/small intestine. Cubn, a scavenger receptor, binds to numerous
ligands; thus, Amn/Cubn may be required during mouse gastrulation for the
uptake of one or more of these from the maternal circulation. Known
Cubn-specific ligands, such as Apoa1/HDL and transferrin, are candidates for
Amn/Cubn transport (Hammad et al.,
1999; Kozyraki et al.,
1999
). However, Apoa1/HDL are not strong candidates for the
crucial Amn/Cubn ligand during murine gastrulation, as
Apoa1-deficient mice are viable and fertile
(Li et al., 1993
;
Williamson et al., 1992
).
Transferrin, however, cannot as yet be ruled out as a crucial Amn/Cubn ligand
in the mouse embryo. As most plasma iron circulates bound to transferrin,
Cubn-mediated uptake of transferrin may release iron and provide it to the
embryo. However, there are other routes for cellular uptake of iron, including
binding of transferrin to the transferrin receptor (Trfr) and Fe3+
transport by the transmembrane iron transporter DMT1
(Andrews et al., 2000
). It is
not known whether DMT1 is active on the apical surface of the VE, but Trfr is
expressed by the mouse yolk sac and a Trfr deficiency results in lethality by
E12.5, with defective erythropoiesis and neurological development
(Andrews et al., 2000
).
Trfr-deficient embryos show signs of anemia only after E10.5, suggesting the
existence of an alternative pathway of iron uptake prior to E10.5, perhaps
Amn/Cubn. Alternatively, it is likely that other, presently unknown,
Cubn-specific ligands are endocytosed/transcytosed by the VE and perhaps one
or more of these are required for normal gastrulation.
Developmental requirements for Amn/Cubn function differ between rodents and human/dog
Although the requirement for Amn/Cubn function in intestine and KPT appears
conserved across mammalian species, the same cannot be said for the role of
Amn during embryonic development. Amn is required during murine gastrulation
for survival; yet humans and dogs have no apparent need for AMN/CUBN until
after birth. While a Cubn-null mutation has not yet been reported in
mouse, antibodies to Cubn, but not to megalin, induce fetal malformations in
rats (Brent and Fawcett, 1998;
Sahali et al., 1988
;
Seetharam et al., 1997
). If
Amn solely functions in a complex with Cubn, Cubn-null mutations in
the mouse will result in a gastrulation phenotype identical to
amn.
The differential requirement for Amn/Cubn during embryogenesis in rodents
versus humans/dogs may reflect anatomical differences in the organization of
extra-embryonic and embryonic tissues, as well as in mechanisms for nutrient
and waste exchange. The murine visceral yolk sac, formed by an outer VE layer
and an inner extra-embryonic mesoderm layer at E7.5, completely surrounds
the developing fetus. It serves as a maternal-fetal interface required for the
exchange of nutrients, oxygen and waste products
(Rossant and Cross, 2002
). By
contrast, the human yolk sac becomes a vestigial appendage attached near the
allantoic mesoderm (Sadler,
1995
), and trophoblast derivatives act as the major maternal-fetal
interface supplying required nutrients and factors. The differences in the
role of the yolk sac between species is exemplified by mutations in ApoB that
cause embryonic lethality in the mouse but fail to affect normal human
development (Farese et al.,
1995
; Hopkins et al.,
1986
; Shi and Heath,
1984
).
Does the amn mutant phenotype result solely from a general nutritional deficiency or does it reflect both the absence of a nutritional factor and a signaling or patterning molecule?
The finding that Amn is a component of an endocytic scavenger receptor
raises the question of whether the distinct features of the amn
mutant phenotype result from a nutritional deficiency that impairs the general
growth of the embryo. Although amn mutants are small, not all tissues
are similarly compromised. The anterior (head, heart, and node derivatives)
and extra-embryonic regions are appropriately specified; yet the middle streak
fails to assemble and trunk mesoderm is never produced
(Tomihara-Newberger et al.,
1998). Thus, this phenotype is unlikely to result simply from an
overall delay in growth.
The amn phenotype is very distinct from those found in other
mutants with defects in VE transport/trafficking functions. Ubiquitously
expressed Sec8 is a member of the Sec6/8 complex, which regulates delivery of
exocytic vesicles to plasma membrane docking sites
(Friedrich et al., 1997). At
E7.5, sec8 mutant embryos are developmentally delayed by
24
hours, but they still express Brachyury (T), a marker of
nascent mesoderm, but not Mox1, a marker for paraxial mesoderm
(Friedrich et al., 1997
),
suggesting either delayed marker expression or simply arrest during
gastrulation (Yeaman et al.,
2001
). A very similar early gastrulation-stage phenotype is
observed in Hnf4-/- embryos. Hnf4, which is expressed
exclusively in VE during gastrulation stages, is a positive transcriptional
activator of genes required for secretion, transcytosis, and digestion
(Duncan et al., 1994
;
Duncan et al., 1997
).
Hnf4 is not required for early specification of VE but is required
for its complete differentiation, as Hnf4-deficient VE fails to
express various VE markers (Duncan et al.,
1997
).
Knockout mutations in mouse Hß58 (Vps26
Mouse Genome Informatics), Snx1 and Snx2 provide further
evidence that transport/trafficking functions are required for midgestation
development. Hß58, expressed at low levels in the epiblast and at high
levels in the VE, is the homolog of yeast Vps26p, a member of the retromer
complex that mediates endosome-to-Golgi trafficking
(Lee et al., 1992;
Seaman et al., 1998
). The
sorting nexins 1 (Snx1) and 2 (Snx2) are homologs of yeast Vps5p, also a
component of the retromer complex (Seaman
et al., 1998
). Snx1-/-; Snx2-/-
double mutants display a phenotype nearly identical to that of
Hß58 mutants, which are visibly growth retarded at
E7.5 and developmentally arrested by E10.5
(Schwarz et al., 2002
). Thus,
Hß58 and Snx1 and Snx2 appear to
function in the same cellular trafficking pathway, which probably acts to
maintain functional integrity of the VE. Notably, despite their severely
retarded growth, and in contrast to amn mutants,
Hß58 and Snx1-/-;
Snx2-/- mutants form derivatives of all three germ layers,
including somites (Radice et al.,
1991
; Schwarz et al.,
2002
).
The sec8 and hnf4 mutant phenotypes are more severe than that of amn, including growth retardation and failure to support gastrulation. The Hb58 and Snx1-/-; Snx2-/- mutant phenotypes, however, are less severe. The mutant embryos are very small but undergo gastrulation and produce trunk mesoderm and somites. Although it has not been determined whether the defects in these mutants are solely the result of blocked endocytosis/transcytosis, the comparison of these mutant phenotypes suggests that the middle streak defects in amn do not simply result from a general delay in embryonic growth. Thus, loss of Amn not only impairs growth of the epiblast, but also disrupts mechanisms for assembling an appropriately patterned and functional middle primitive streak. A question for future studies is how, via endocytosis, transcytosis, and/or signaling, Amn/Cubn promotes and coordinates growth and patterning of the mouse gastrula.
In summary, Amn mediates Cubn localization and function in the mouse, which argues for an essential role of Amn/Cubn-directed endocytosis/transcytosis in the VE during gastrulation. We are currently considering two general models to explain the combined defects in growth and middle primitive steak assembly/function in the amn mutant. In the first model, Amn/Cubn-mediated endocytosis/transcytosis in the VE may provide nutrient(s) to the epiblast that are essential for cell proliferation and growth. However, loss of Amn would not equally compromise all proliferating epiblast cells; those that assemble into the middle streak, thereby physically separating distal and proximal streak regions, would be the most severely affected. In the second model, Amn/Cubn-mediated endocytosis/transcytosis in the VE, in addition to providing essential nutrients required for general growth, would facilitate/modulate key signaling pathways required for specification of the middle streak and its derivatives. Further dissection of the amn mutant phenotype and the nature of the requirement for Amn during gastrulation will provide insight into the role of the VE in murine development and highlight similarities and differences in gastrulation between species.
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ACKNOWLEDGMENTS |
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