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Blood, Vol. 94 No. 1 (July 1), 1999:
pp. 127-138
By
From the Departments of Microbiology and Biochemistry and Centre for
Molecular and Cellular Biology, University of Queensland, Queensland,
Australia; the Department of Molecular Genetics, Ohio State University,
Columbus, OH; and the Burnham Institute, La Jolla, CA.
During mouse embryogenesis, macrophage-like cells arise first in the
yolk sac and are produced subsequently in the liver. The onset of liver
hematopoiesis is associated with the transition from primitive to
definitive erythrocyte production. This report addresses the hypothesis
that a similar transition in phenotype occurs in myelopoiesis. We have
used whole mount in situ hybridization to detect macrophage-specific
genes expressed during mouse development. The mouse c-fms mRNA,
encoding the receptor for macrophage colony-stimulating factor (CSF-1),
was expressed on phagocytic cells in the yolk sac and throughout the
embryo before the onset of liver hematopoiesis. Similar cells were
detected using the mannose receptor, the complement receptor (CR3), or
the Microphthalmia transcription factor (MITF) as mRNA markers.
By contrast, other markers including the F4/80 antigen, the macrophage
scavenger receptor, the S-100 proteins, S100A8 and S100A9, and the
secretory product lysozyme appeared later in development and appeared
restricted to only a subset of c-fms-positive cells. Two-color
immunolabeling on disaggregated cells confirmed that CR3 and c-fms
proteins are expressed on the same cells. Among the genes
appearing later in development was the macrophage-restricted
transcription factor, PU.1, which has been shown to be required for
normal adult myelopoiesis. Mice with null mutations in PU.1 had normal
numbers of c-fms-positive phagocytes at 11.5dpc. PU.1(
THE MONONUCLEAR phagocyte system is
defined as a family of cells that arise from hematopoietic progenitors
in bone marrow and progress through monoblasts and promonocytes to
monocytes.1 At this stage, they enter the circulation and
migrate into the tissues to become mature macrophages. The production
of monocytes and macrophages in adult mice is controlled by macrophage
colony-stimulating factor (M-CSF or CSF-1),2 which acts
through a specific plasma membrane receptor encoded by c-fms
proto-oncogene.3,4 Granulocyte-macrophage colony-stimulating factor, interleukin-3 (IL-3), and many other cytokines/lymphokines can regulate monocytopoiesis in vitro or in
vivo.5,6
Electron microscopic studies of early embryonic development have
identified the first cells with the ultrastructural appearance of
tissue macrophages in the yolk sac before they appear in the embryo.
Putative phagocytes infiltrate the head and much of the rest of the
body at the same time as the first pluripotent hematopoietic progenitor
cells can be detected in the aorta-gonad-mesonephros (AGM) and
subsequently in the liver7,8; that is, around 10 days
postcoitum (dpc). The origin of early embryonic phagocytes in the yolk
sac has been demonstrated most convincingly via the use of chick-quail
chimeras.9 Yolk sac "macrophages" appear to develop
without passing through an obvious monocyte stage, as evidenced by the
lack of markers such as peroxidase and the monocyte surface marker,
ER-MP20, and continue to proliferate actively once they have
infiltrated the embryo.10,11 Within the embryo,
macrophage-like cells are associated with the rapid removal of
apoptotic cells,12-15 perhaps the most striking example being in the region between the developing digits.16
Removal of dying cells by specialized, migratory phagocytes is a
function conserved across evolution; mechanisms and receptors
identified in Drosophila and Caenorhabditis elegans
have clear parallels in mice. Drosophila hemocytes that remove
dying cells, like mammalian phagocytes, express a CD36 family member
and scavenger receptors.17-19 The mouse homolog of C
elegans cell death gene ced-7 is expressed in fetal
phagocytes and is required for removal of dying cells.20 Evidence from Drosophila21,22 to
mouse12 indicates that cell death precedes macrophage
infiltration, and that dying cells can influence migration and
differentiation of the macrophage-like cells. Apart from the obvious
role in clearance, fetal phagocytes are very closely associated with
the developing vasculature23 and may control angiogenesis
as they do in adults.
The first documented surface marker for the appearance of
macrophage-like cells in the mouse was the F4/80 antigen, an unusual member of the serpentine receptor family of unknown
function.24 Immunocytochemical localization of F4/80 showed
positive cells in the yolk sac and head around 10.5 dpc and
subsequently identified phagocytes in regions of tissue turnover and
cell death.13 We subsequently applied the technique of
whole mount in situ hybridization to localize c-fms mRNA. Cells
with detectable levels of c-fms mRNA appeared simultaneously in
the yolk sac and the embryo around 9.5 dpc. Later they were not only
associated with presumptive hematopoietic cells in the developing
liver,25 but were also observed throughout the body of the
developing embryo, with particularly high frequency found in the sites
of known tissue turnover including interdigital spaces and the brain.
More recently, the The differentiation of myeloid cells is controlled by specific
transcription factors. The first exon of the murine and human c-fms gene that is transcribed in macrophages is flanked by a promoter that contains binding sites for the myeloid-restricted transcription factor PU.1.27-30 We have recently shown that
these sites alone constitute a macrophage-specific minimal
promoter.31 Similar binding sites are present in promoters
of other macrophage-restricted genes, including tartrate resistant acid
phosphatase (TRAP), lysozyme M, macrophage scavenger receptor, IL-1 Animals
Embryonal stem (ES) cells culture and differentiation.
D3 parent ES cells and PU.1(+/ Latex beads phagocytosis assay.
Latex beads (1.16 µm in diameter) (Sigma) were purchased as 10%
(wt/vol) aqueous suspension. They were washed and resuspended in
sterile phosphate-buffered saline (PBS) at the same concentration. The
beads were added to the cells at a final concentration of 0.01%
(wt/vol), and the cells were incubated at 37°C, 5%
CO2, and monitored for phagocytosis between 1 and 4 hours.
The cells were then washed twice with PBS and fixed in 1%
glutaraldehyde (Sigma) for 30 minutes at room temperature, washed twice
with PBS, and stored in fresh PBS at 4°C.
In situ hybridization.
The probes were made and labeled using digoxygenin (DIG) RNA labeling
mix according to the manufacturer's instructions (Boehringer Mannheim,
Mannheim, Germany), using T7 and T3 polymerases from Promega (Madison, WI), and Sp6 from Boehringer Mannheim.
Probes were stored at
Histology
Immunocytochemistry ES cell-derived macrophages were fixed in 4% PFA/PBS (Sigma) for 30 minutes at room temperature. The cells were then washed in PBS and incubated with ice-cold methanol containing 0.5% (vol/vol) H2O2 to quench any endogenous peroxidase activity. Nonspecific protein binding was blocked by incubating the cells with 10% FCS in PBS for 10 minutes at room temperature. The primary rat antimouse F4/80 antibody (as rat hybridoma supernatant) was diluted 1:100 in PBS containing 10% FCS and then added to the cells for 60 minutes at room temperature. The primary antibody was detected with a secondary antirat horseradish peroxidase-linked antibody for 60 minutes at room temperature. A solution of 0.5 mg diaminobenzidine (DAB) substrate/mL (Sigma) supplemented with 1 µL/mL of 30% H2O2 was added to detect the antibody for a maximum of 10 minutes. Cells were monitored during this time for the emergence of an orange-brown stain, which indicated the presence of the surface antigen F4/80.Photography Photographs of whole mounts were taken on a Leica dissecting microscope with cold lamp side illumination using Kodak T64 film. Photographs of sections were taken on an Olympus AX70 microscope using Kodak daylight film under Nomarski optics (unstained) or bright field (stained sections), and finally the photographs of cells in culture were taken on an inverted Olympus microscope using Kodak T160 film and Nomarski optics.Flow Cytometry Embryos were disaggregated using a modified method of Yoder et al.44 Briefly, the yolk sacs (10 to 13.5 dpc), embryos (10.0 and 11.5 dpc), or fetal livers (10.5 to 12.5 dpc) were dissected free and washed in PBS. They were then drawn through an 18G (yolk sacs 11.5 to 13.5 dpc) or 23-gauge needle and transferred to a petri dish and incubated with 0.1% collagenase D; 0.2% dispase (Boehringer) in PBS/20%FCS for 60 minutes at 37°C. Dispersed cells were drawn through a 23-gauge needle into a syringe, pelleted by centrifugation, washed in PBS, and counted. If required, the cells were cultured in medium containing 5 × 103 Cetus U/mL of recombinant human CSF-1 (Chiron Corp) in bacteriological petri dishes.45
Location of c-fms-Positive Cells by Whole-Mount In Situ Hybridization Shows a Large Population of Phagocytes in the Embryo The detection of c-fms-positive cells in the developing mouse embryo by in situ hybridization was reported previously.25 Although it was inferred, no independent marker or phenotypic characteristic confirmed the identity of c-fms-positive cells as phagocytes. As a baseline for the examination of other putative macrophage markers, we performed a more extensive analysis of the appearance of this marker. Cells expressing c-fms mRNA were detected first in the yolk sac at 9.5 dpc as isolated individual cells rather than clusters associated with blood islands, which develop in the yolk sac at 8.0 to 8.5 dpc. Among numerous embryos examined, we have never observed any in which the first appearance of c-fms-positive cells in the head of the embryo is clearly delayed relative to the yolk sac. Assuming the cells are first formed in the yolk sac, the infiltration into the embryo must occur almost immediately. Figure 1A shows an embryo at 10 dpc, in which positive cells are evident in the head. In some embryos at this time, c-fms-positive cells are particularly concentrated in a band overlying the developing heart (not shown; but see a similar pattern with the MITF gene in Fig 4F). By 10.5 dpc, c-fms-positive cells were first detected in the liver (Fig 1B), consistent with the appearance of macrophage-like cells defined by other criteria.13 Macrophages have been shown previously to be actively involved in removing apoptotic cells to form a foot with separate digits.16,20 To assess whether c-fms mRNA was associated with fetal phagocytes, we concentrated particularly on the distribution in this site. The infiltration of the limb buds by c-fms-positive cells was actually evident well before the onset of cell death between the digits, at 10.5 dpc, when they accumulate in the apical ectodermal ridge (AER). At 12.5 dpc, c-fms-positive cells still delineated the AER and they also accumulated in the anterior "necrotic" zone (Fig 1C). When the cell death commences between the digits, c-fms provides a clear marker for phagocytic cells that infiltrate the interdigital region from the marginal sinus (Fig 1D). At higher magnification, many c-fms-positive cells in this site contain inclusions of ingested pyknotic nuclei (not shown).
c-FMS Protein Is Coexpressed on Isolated Embryonic Cells With Other Myeloid Markers, Mac-1 (CR3) and F4/80 Whole-mount in situ hybridization is difficult to adapt to simultaneous localization of more than one marker on a dispersed population of cells. As an independent way to confirm that the protein product of c-fms mRNA is expressed and that it is coexpressed with other myeloid markers, we digested embryos with collagenase and dispase and examined the expression of surface markers by flow cytometry. Cells were isolated from the embryonic liver and the remainder of the embryo at 10.5 dpc and analyzed by double-labeling with an anti-c-fms monoclonal antibody in combination with either anti-F4/80 or anti-Mac-1 (which recognizes the type III complement receptor, CR3). At 10.5 dpc, in the liver (Fig 2), just over 50% of the c-fms-positive cells also expressed detectable F4/80, and more than 60% coexpressed Mac-1. In nonhepatic tissues, the proportion of c-fms-labeled cells (1.5% to 2.0% of the total) was greater than in the liver as expected from the mRNA localization. Consistent with the localization of the F4/80 mRNA, less than 20% coexpressed detectable F4/80 antigen, and even in these, the level of expression was very low. By contrast, more than 70% coexpressed high levels of Mac-1. Compared with the remainder of the embryo, the liver was enriched for a population of cells that expressed Mac-1, but not c-fms, which probably reflects early stages of granulocyte differentiation. In cells isolated from both the liver and embryo, the percentage of cells coexpressing c-fms with F4/80 or Mac-1 was increased by overnight culture in CSF-1 containing medium (data not shown). This observation could be due to cell growth and/or reversal of the partial loss of these surface markers during enzymatic digestion and isolation. For this reason, the analysis cannot be viewed as quantitative and serves primarily to prove that the majority of c-fms-positive cells also express other myeloid cell markers.
Mannose Receptor mRNA Colocalizes With c-fms, Whereas the Scavenger Receptor mRNA Is Restricted to a Subset of Phagocytes The coexpression of Mac-1 antigen (CR3) with c-FMS antigen shows that at least some of the embryonic phagocytes have endocytic receptors in common with adult macrophages. To extend knowledge of the endocytic capacity of embryonic phagocytes, we localized the macrophage mannose receptor (MMR)49 and macrophage scavenger receptor (MSR)50 in embryos from 9.5 to 13.5 dpc. At all stages examined, MMR-positive cells were as abundant in the yolk sac and embryo as c-fms-positive cells and the perivascular locations and cellular morphologies of labeled cells were indistinguishable either at the gross level (Fig 3A and B) or on examination of sections (not shown). By contrast, MSR mRNA expression was much more restricted. Positive cells were detected in the heart, liver (Fig 3C), limb buds, and all over the body, but the numbers were clearly less than observed using c-fms or MMR probes and the expression appeared restricted to larger cells, more closely resembling the abundance of F4/80. Examination of sections of these embryos confirmed a distribution and morphology of MSR-positive cells consistent with restriction to larger c-fms-positive cells that are actively involved in phagocytosis of pyknotic cells (Fig 3D; compare with Fig 1G and H).
PU.1 mRNA Is Not Expressed at Detectable Levels in All Embryonic Phagocytes As noted earlier in this report, the Ets family of transcription factors is implicated in myeloid differentiation. Clearly, if PU.1 controls the differentiation of fetal phagocytes, it should be expressed before c-fms and other myeloid markers. Whole-mount in situ hybridization failed to detect any PU.1-positive cells at 9.5 dpc in the yolk sac or embryo (not shown) where c-fms is readily detected (Fig 1A). In fact, cells expressing PU.1 mRNA were not detectable until the onset of liver hematopoiesis (Fig 4A and B). It must be emphasized that the absence of detectable PU.1 mRNA in the earlier embryo does not indicate total absence and is clearly constrained by the sensitivity of the method. In all experiments, embryos are incubated in the staining reagents until any signal detected becomes maximal, or the background "nonspecific" staining becomes evident. A number of cells detected in the liver at this time were clearly phagocytic, suggesting that the populations of PU.1 and c-fms-positive cells do overlap, but c-fms is more widespread (Fig 4C). Apart from the absence of detectable PU.1 in the yolk sac, PU.1 mRNA was detectable in considerably fewer cells in the brain than c-fms, although the signal intensity was comparable where it was expressed (not shown). Another site in which it was clear that PU.1 was not detectable in all c-fms-expressing cells was the limb. The first detectable PU.1-positive cells in the distal part of the limbs appeared at 12.5 dpc (c-fms cells were detectable there from 10.5 dpc) and remained at the margins (Fig 4D) at the time when c-fms-positive phagocytes had already invaded the interdigital spaces (see Fig 1C). This pattern of PU.1 expression in the limb buds was very similar to that of MSR, which also accumulates at the limb bud margins comparatively late at 12.5 dpc. In summary, PU.1 mRNA is not expressed at detectable levels in all c-fms-positive cells, and the pattern of expression is consistent with restriction to a subset of cells arising later in development.
MITF Is an Early Phagocyte Marker Of the markers examined thus far, only c-fms, MMR, and CR3 appear to be expressed on early phagocytes. Presumably, the expression of these genes is controlled by transcription factors expressed specifically in these cells. Other than PU.1, there are few transcription factors known to be restricted to the macrophage lineage. Other studies in our laboratory have implicated factors in the basic helix-loop-helix-ZIP family in transcriptional regulation of macrophage-specific genes, including c-fms. Among this family, mutations in the MITF have been shown to cause osteopetrosis, a phenotype also associated with deficiency in CSF-1. Like the PU.1 transcription factor, MITF has been shown to be expressed in adult macrophages and osteoclasts.51 We, therefore, investigated whether MITF mRNA is also expressed in the embryo. Figure 4E and F shows that MITF mRNA, like c-fms mRNA, was detectable on numerous cells in yolk sac and at the same time in the head and in the characteristic band of cells above the early developing heart. The location, morphology, and apparent phagocytic activity of the labeled cells was consistent with identity or substantial overlap of the MITF and c-fms-expressing populations.Identification of Additional Markers Associated With the Onset of Hematopoiesis in the Embryonic Liver The secretory product, lysozyme, is widely expressed in macrophages in adult mice. In the embryo, lysozyme mRNA was not detectable in the yolk sac or embryo until 10.5 dpc, when its expression was restricted to sparse large cells in the liver (Fig 5A). From 11.5 dpc, lysozyme-positive cells were present outside the liver, but were not as abundant as even MSR-positive cells. Sections of the stained embryos indicated heterogeneous levels of expression of the gene, with strongly and weakly positive cells. The former were generally larger cells, examples were observed in greatest concentration in the pericardial wall, the peritoneal cavity, and also in the sinusoids of the liver, and many were clearly actively involved in phagocytosis of dying cells (Fig 5B).
The Presence of Phagocytes in PU.1(
Differentiation of PU.1(
The Expression of c-fms Is a Marker for Early Fetal Phagocytes
The Onset of Myelopoiesis in Liver Correlates With Altered Expression of Macrophage-Specific Genes In contrast to c-fms, MMR, MITF, and CR3, several markers characteristic of adult macrophages, were only detected once hematopoiesis was established in the liver. The mRNA encoding the S-100 proteins, S100A8 and S100A9, was shown to be transiently expressed in presumptive myeloid progenitor cells only in the liver, providing a striking marker of this transition. F4/80 antigen was apparently another late marker. Previous descriptions of embryonic mononuclear phagocytes used F4/80 antibody.13 The gene was cloned only recently and encodes an integral membrane protein of unknown function.24 Both FACS analysis (Fig 2) and whole mount in situ hybridization indicated that c-fms, MMR, and Mac-1 expression precedes the appearance of F4/80, and that the F4/80 antigen is probably absent, or at very low levels, on yolk sac-derived phagocytes. The patterns of expression of two other late markers, the secretory product lysozyme and MSR (Figs 3 and 5) were broadly similar to that of F4/80, although both mRNAs appeared particularly evident on large cells involved in active phagocytosis. The function of MSR in embryonic phagocytosis appears to be conserved during evolution, as the phagocytes in Drosophila also express a form of scavenger receptor.18,19 This function is not indispensable because scavenger receptor null mice do not have developmental abnormalities.57,58 Association of lysozyme expression with phagocytosis is compatible with its apparent function in adult mice59 and the low expression of lysozyme in the fetal macrophages has also been reported by others.60PU.1 Transcription Factor Is a Late Marker and Is Not Required for Embryonic Phagocyte Production The PU.1 null mutation in mice had no discernible effect on the number or distribution of c-fms-positive phagocytes at 11.5 dpc (Fig 7). Olson et al41 used semiquantitative RT-PCR to examine gene expression in an independent line of PU.1 null animals and found not only c-fms, but also CD11b and CD18 (which make up Mac-1 antigen, shown to be coexpressed with c-fms in our study) and GM-CSF receptor were unaltered at this early stage of development. Hence, although there are some differences in the hematopoietic phenotypes and viability of the two published lines of PU.1( /) mice,39-41 both probably retain the
phagocytes we have defined. We have not performed marker studies later
in development, but the morphogenic processes that appear to involve
fetal phagocytes occur normally in the PU.1(/) null
embryos. For example, the digits are formed normally, and in
histological sections at 12.5 to 13.0 dpc, phagocytes can be seen
between the digits internalizing pyknotic nuclei (not shown). The lack
of effect of the PU.1 null mutation on early embryonic phagocyte
production is consistent with the distribution of PU.1 mRNA, which was
not detected until the onset of liver hematopoiesis and even
thereafter, in locations such as the footpad, was detected in only a
subset of cells expressing c-fms and other early markers. Our
conclusion that PU.1 is not required for embryonic phagocyte production
is not incompatible with published evidence that it is absolutely
required for "definitive" myelopoiesis. In fact, there is general
agreement that the ability of the fetal liver to produce
monocyte-macrophage progenitor cells and to respond to hematopoietic
growth factors such as G-CSF, GM-CSF, and CSF-1 is almost completely
compromised by the PU.1 null mutation.61-64 These studies
involve in vitro colony assays, and the analysis of embryos later in
development (>14.5 dpc) when PU.1 is normally expressed at readily
detectable levels in the liver.
Transcription of Macrophage-Specific Genes Is Not Absolutely PU.1-Dependent The presence of c-fms-expressing phagocytes in the PU.1 (/) mice indicates that PU.1 cannot be absolutely
required for transcription of the c-fms gene itself. By
contrast, deKoter et al64 reported that
c-fms expression was greatly reduced in myeloid progenitor cells isolated from 14.5 dpc PU.1(/) fetal livers, and
that retroviral transduction of c-fms partly rescued the
ability of the cells to proliferate, but not to differentiate, in
response to CSF-1. The apparent reduction in c-fms expression
in these studies was measured by PCR in purified lin
progenitor cells. It remains possible that the investigators could have
detected normal expression of c-fms in the lin+
population of fetal liver cells from PU.1(/) animals, as
demonstrated from our observations. Furthermore, the possibility that
the PU.1 null mutation alters the distribution of c-fms
expressing cells between lin+ and lin
populations was not excluded. The low c-fms expression and
CSF-1 unresponsiveness of the lin cells in these
studies might be an indirect consequence of lack of expression of the
GM-CSFR. We and others have shown that optimal proliferation of murine
macrophage progenitors requires cooperation between GM-CSF and
CSF-1.65 Hence, the published data do not demonstrate
unequivocally that PU.1 directly controls c-fms transcription even in adult hematopoiesis. Both the mouse and human c-fms
promoters have multiple functional binding sites for this factor in
the proximal promoter,28,30,31,66 but neither promoter is
absolutely PU.1-dependent, and both can be activated by other members
of the Ets transcription factor family such as Ets-2.31
Additionally, both human67 and mouse (J. Pollard, personal
communication, July 1997) c-fms genes are
expressed in trophoblasts from separate promoters that might also be
used by fetal phagocytes.
What Happens to PU.1-Independent Phagocytes? Both lines of PU.1(/) mice lack mature macrophages as
evidenced by localization of mature macrophage markers such as
F4/80,39-41,61-64 but embryonic development and
organogenesis occurs relatively normally. Based on the data presented
here, we hypothesize that PU.1-independent phagocytes are retained
throughout development and carry out their function normally in the
null mice. If that view is correct, PU.1-independent macrophages could
be retained in the adult. In fact, there is no published evidence that
PU.1 is expressed in all adult tissue macrophages. The PU.1-independent macrophages could be the same as the so-called CSF-1-independent macrophages that develop in the op/op mouse.71 If
they retain their ability to proliferate locally within
tissues,72-75 they could represent a pool of precursors of
resident tissue macrophages in the adult and therefore be quite
distinct from the inflammatory macrophages derived from circulating
blood monocytes in the normal steady state. Recent data using marrow
transplanted from mice with an integrated lacZ reporter gene supports
the view that some macrophage pools are very slowly infiltrated by
cells derived from the blood.76 Such a proposal clearly
undermines the basic concept of the mononuclear phagocyte system,
namely that tissue macrophages derive from blood monocytes, which in
turn come from marrow progenitors,1 but it might provide
some additional insight into the origins of macrophage heterogeneity.
Submitted October 29, 1998; accepted March 3, 1999.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. section 1734 solely to indicate this fact.
Address reprint requests to Professor David A. Hume, PhD, Department of Microbiology, University of Queensland, Queensland 4072, Australia; e-mail: D.Hume{at}cmcb.uq.edu.au.
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  R. M. B. Costa, X. Soto, Y. Chen, A. M. Zorn, and E. Amaya spib is required for primitive myeloid development in Xenopus Blood, September 15, 2008; 112(6): 2287 - 2296. [Abstract] [Full Text] [PDF]
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J. Y. Bertrand, A. Jalil, M. Klaine, S. Jung, A. Cumano, and I. Godin Three pathways to mature macrophages in the early mouse yolk sac Blood, November 1, 2005; 106(9): 3004 - 3011. [Abstract] [Full Text] [PDF]
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W Wood, M Turmaine, R Weber, V Camp, R. Maki, S. McKercher, and P Martin Mesenchymal cells engulf and clear apoptotic footplate cells in macrophageless PU.1 null mouse embryos Development, January 12, 2000; 127(24): 5245 - 5252. [Abstract] [PDF]
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 A. Luchin, S. Suchting, T. Merson, T. J. Rosol, D. A. Hume, A. I. Cassady, and M. C. Ostrowski Genetic and Physical Interactions between Microphthalmia Transcription Factor and PU.1 Are Necessary for Osteoclast Gene Expression and Differentiation J. Biol. Chem., September 21, 2001; 276(39): 36703 - 36710. [Abstract] [Full Text] [PDF]
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| Copyright © 1999 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
TOP
ABSTRACT
INTRODUCTION
2 integrin, CD11b (Mac-1), was localized in the
embryo in a pattern that appears roughly consistent with
c-fms.
RI and Fc
