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Blood, Vol. 94 No. 2 (July 15), 1999:
pp. 818-824
Expression of the Fanconi Anemia Group A Gene (Fanca)
During Mouse Embryogenesis
By
Radwan Abu-Issa,
Gregor Eichele, and
Hagop Youssoufian
From the Departments of Molecular and Human Genetics, Biochemistry,
and Medicine, and the Developmental Biology Program, Baylor College of
Medicine, Houston, TX.
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ABSTRACT |
About 80% of all cases of Fanconi anemia (FA) can be accounted for
by complementation groups A and C. To understand the relationship between these groups, we analyzed the expression pattern of the mouse
FA group-A gene (Fanca) during embryogenesis and compared it
with the known pattern of the group-C gene (Fancc). Northern analysis of RNA from mouse embryos at embryonic days 7, 11, 15, and 17 showed a predominant 4.5 kb band in all stages. By in situ hybridization, Fanca transcripts were found in the whisker
follicles, teeth, brain, retina, kidney, liver, and limbs. There was
also stage-specific variation in Fanca expression, particularly
within the developing whiskers and the brain. Some tissues known to
express Fancc (eg, gut) failed to show Fanca
expression. These observations show that (1) Fanca is under
both tissue- and stage-specific regulation in several tissues; (2) the
expression pattern of Fanca is consistent with the phenotype of
the human disease; and (3) Fanca expression is not necessarily
coupled to that of Fancc. The presence of distinct tissue
targets for FA genes suggests that some of the variability in the
clinical phenotype can be attributed to the complementation group assignment.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
PATIENTS WITH FANCONI anemia (FA) suffer
from a wide variety of congenital abnormalities. The spectrum of these
abnormalities includes growth retardation, skin hyperpigmentation,
radial ray deformities, hypogonadism, renal malformations,
microcephaly, variable degrees of mental retardation, and
microphthalmia.1,2 However, there is extensive phenotypic
variability. Also, because many patients develop cytopenias and
malignancies,3 FA is regarded as an important genetic model
of hematopoietic failure and cancer susceptibility. Cellular
manifestations of FA include chromosomal instability, an enhanced
sensitivity to bifunctional alkylating agents (eg, mitomycin C [MMC])
and to oxygen, delay in the G2 phase of the cell cycle, and a
predisposition to apoptosis.(Kruyt and Youssoufian4 and
references therein)
FA is genetically heterogeneous and has been subdivided into at least
eight complementation groups.5,6 All subtypes are autosomal
recessive. The disease-associated genes for complementation groups C
(FANCC),7 A (FANCA),8,9 and G
(FANCG)10 have been cloned and shown to encode
distinct and novel proteins. In all three cases, the sequences of the
predicted polypeptides have failed to suggest a particular function or
show any shared motifs. Thus, the ~63 kD FANCC protein is homologous
neither to the ~163 kD FANCA protein nor to the ~70 kD FANCG
protein (also called XRCC9).
In the absence of such clues from the primary sequences, some of our
current understanding about the molecular function of FA gene products
has emerged from studies of their cellular localization, protein
interactions, and expression patterns. Several studies have shown that
FANCC localizes primarily to the cytoplasm under both steady-state and
stress conditions.11-14 Other studies have also reported
that a fraction of FANCC localizes to the nucleus.15,16 Because targeting of FANCC to the nucleus abolishes its ability to
correct the hypersensitivity of FA group-C cells to MMC,14 its major biological function is most likely performed in the cytoplasm. Consistent with this model is our recent observation that
FANCC binds to the microsomal enzyme NADPH cytochrome P450 reductase
and regulates its activity, which suggests that FANCC plays a role in
detoxification.17 FANCA is localized in both the nucleus
and cytoplasm4,15 and functions in a cell compartment distinct from FANCC.4 Forced targeting of FANCA to the
cytoplasm abolishes its ability to correct the hypersensitivity of FA
group-A cells to MMC.4 Therefore, unlike FANCC, FANCA works
in the nucleus. Two reports have also claimed that FANCA interacts
physically with FANCC,15,18 but we have been unable to
confirm these results.4 Although FANCA has limited homology
to a class of peroxidases,19 its precise function remains unknown.
As expected from the pleiotropic nature of FA mutations, both
FANCA and FANCC are thought to be expressed in many
tissues, albeit at low levels.4,7-9,12 In situ
hybridization studies of the murine Fancc gene has shown that
it is expressed initially (embryonic [E] days 8 to 10) in the
mesenchyme and its derivatives with osteogenic potential, and at later
stages (E 13-19.5) in other cells involved in bone
development.20 Fancc expression was also observed
in the brain, whisker follicles, lung, kidney, gut, and
stomach.20,21 We therefore reasoned that a comparison of
the expression pattern of Fancc with that of Fanca
might clarify the functional relationship between these subgroups and
show tissue targets that are differentially sensitive to FA mutations.
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MATERIALS AND METHODS |
Cloning of murine Fanca cDNA sequences.
A segment of the murine Fanca complementary DNA (cDNA) was
amplified by polymerase chain reaction (PCR) from two different cDNA
libraries derived from murine erythroleukemia cells and normal murine
thymocytes (Youssoufian, unpublished). The following oligonucleotide primers were used for PCR amplification: Fanca1,
5'-CAGACACTGACAGAATGCCAGACTAAG; and Fanca2,
5'-CTGAGGTATTAGCTGCAGCAGAAAAAC. The Fanca1 primer was based on
the sequence of the expressed sequence tags (EST) AA146162, and
the Fanca2 primer was based on the sequence of the EST AA171025. The
PCR-derived fragments were blunt-ended and cloned in pBluescript KS+.
Northern analysis.
A Northern blot containing approximately 2 µg of poly A+
RNA per lane from mouse embryos at four different stages of development was probed using conditions recommended by the manufacturer (Clontech, Palo Alto, CA). To improve the detection of Fanca, the 752 bp fragment was labeled simultaneously with both
[ -32P]dCTP and [-32P]dATP.
RNA in situ hybridization.
Embryo collection, sectioning, and in situ hybridization were performed
as described.22 Antisense and sense RNA probes of the mouse
Fanca cDNA corresponding to nucleotides 3491 to 4258 of the
human FANCA cDNA were synthesized with T7 or T3 RNA polymerase and labeled with 35S-UTP (1000 Ci/mmol; Amersham,
Arlington Heights, IL). Hybridization was done overnight at 50°C.
The probe concentration was 0.09 ng/mL. Posthybridization treatments
were as follows: (1) one wash in 50% formamide, 2× sodium
chloride-sodium citrate (SSC), 20 mmol/L  -mercaptoethanol (FSM) at
50°C for 30 minutes, (2) digestion with 20 µg/mL ribonuclease A
in 4× SSC, 20 mmol/L Tris-HCl (pH 7.6), 1 mmol/L EDTA at 37°C
for 30 minutes, and (3) one wash in FSM at 58°C for 30 minutes.
Slides were dipped in Kodak NTB-2 emulsion (Kodak, Rochester,
NY) and exposed for 9 days. Tissues were visualized by
fluorescence of Hoechst dye-stained nuclei. Silver grains were
visualized with darkfield microscopy. Digital images were captured
using a video camera and Adobe Photoshop 3.5 software (Adobe Systems
Inc, San Jose, CA) on a Macintosh computer (Apple, Cupertino, CA).
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RESULTS |
Cloning of mouse Fanca cDNA.
The human FANCA gene consists of 43 exons dispersed over ~80
kb of genomic DNA.23,24 The structure of the murine
Fanca gene has not yet been determined. Using sequence
information from the EST database, we screened two cDNA libraries from
erythroleukemia cells and thymocytes and obtained the same-sized
fragment of 742 bp. Sequencing of multiple independent clones showed
that the insert corresponds to the human FANCA cDNA residues
3491 to 4258.8 The endpoints of the cDNA fragment fall
within exons 35 and 42 of the human FANCA
gene.23,24 The sequence also matched with the sequences of
EST AA146162 and AA171025 and showed an overall identity of 70% to the
nucleotide sequence of the human FANCA cDNA. The labeled insert
was then used to isolate a full-length cDNA clone by colony
hybridization (complete nucleotide sequence in preparation).
Analysis of Fanca gene expression.
Using the 742 bp fragment as a probe, we analyzed the expression of
mouse Fanca during four different stages of embryogenesis. A
predominant 4.5 kb band was observed as early as E7, and expression was
maintained throughout embryogenesis (Fig
1). The same Northern blot probed with a longer cDNA fragment
corresponding to the human FANCA cDNA nucleotides 2101-4491 (spanning exons 23-43) showed the same 4.5 kb band, although additional
smaller bands were detected at reduced stringency (data not shown).
However, as tissue-specific and temporal variations in expression
cannot be readily detected by this analysis, we performed in situ
hybridization at different stages of mouse development, including
E10.5, E13.5, E16.5, and neonatal (P0) stages.
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| Fig 1.
Northern blot of poly A+ RNA from the
developing mouse. A 742 bp fragment of mouse Fanca cDNA
spanning exons 35 to 42 of the corresponding human FANCA gene
and the human  -actin cDNA were used as probes. The top blot was
exposed for 4 days, whereas the bottom blot was exposed for 6 hours.
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Expression in the whisker follicles.
Whiskers or vibrissae are large sensory hairs around the mouth. These
structures develop at about E12 with the initial formation of an
epithelial placode followed by the formation of dermal papillae (E13-14).25 The papillae surround epithelial placodes,
after which the epithelial cells form hair and the hair sheath
(E14-17). Hair emerges from the skin at E17.5, which completes the
formation of whisker follicles. At E13.4, Fanca is expressed in
the forming placode and dermal papilla (arrows in
Fig 2A). This expression is maintained at
later embryonic stages (E16, not shown), but at the neonatal P0 stage
it becomes more restricted to the dermal papilla (Fig 2B).
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| Fig 2.
Expression of Fanca in developing hair follicles
(arrows) at (A) E13.5 and (B) P0 stages probed with antisense probes.
Controls with sense probes for each panel are shown (A',
B').
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Expression in the brain.
Beginning at E8-9, the neural tube closes and begins to bulge and
constrict, which gives rise to the different portions of the brain
(fore-, mid-, and hindbrain). The optic vesicles form as secondary
outgrowths from the forebrain during embryogenesis and then go on to
form the retina during the postnatal period (P0-P16). The forebrain
gives rise to the cerebral cortex, olfactory bulb, and hippocampus.
Cells in the cerebral cortex proliferate in the ventricular zone, and
at E12 begin to migrate within the intermediate zone and give rise to
the cortical plate.26 The cerebellum develops between the
mid- and hindbrain as early as E13, but most of the proliferative and
migratory activities take place postnatally between P0 and
P21.27 At E13.5, Fanca expression is limited to the
intermediate zone of the developing cerebral cortex
(Fig 3A) and the anterior part of the
midbrain (Fig 3B), which give rise to the tectum. By the P0 stage,
Fanca expression is no longer detectable at these sites (data
not shown). Instead, Fanca transcripts now become detectable in
the external granular layer of the cerebellum (Fig 3C) and in the inner
nuclear layer of the developing retina (Fig 3D) in concert with the
postnatal maturation of these organs.
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| Fig 3.
Expression of Fanca in the developing brain at
E13.5 (A) within the intermediate zone of the cerebral cortex and (B)
the anterior part of the midbrain, and at the P0 stage in (C) the
external granular layer of the cerebellum and (D) the inner nuclear
layer of the developing retina. Controls are shown as indicated in Fig
2.
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Expression in the liver.
The liver arises at E9 from the hepatic diverticulum. By E11.5,
hematopoietic foci are found intermingled with the hepatic cords.28 Fanca expression is readily detectable at
E13.5 in a diffuse pattern (Fig 4A), which
makes it difficult to identify the particular lineages of the
Fanca-positive cells. The expression of Fanca is
significantly lower at the P0 stage, although it can still be detected
(Fig 4B).
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| Fig 4.
Expression of Fanca in the liver (A) at E13.5 and
(B) the P0 stage. Controls are shown as indicated in Fig 2.
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Expression in the kidney, teeth, and limbs.
Kidney development begins at E10 as a result of an interaction between
two mesodermal derivatives, the ureteric bud, and the metanephric
mesenchyme.29 Through the second half of gestation the
ureteric bud grows, branches, and makes connections with the maturing
nephric tubules that form the renal collecting duct system. Fanca expression appears as early as E16 in the developing
ducts (not shown). At P0, there is a high level of expression in the epithelial cells of the developing collecting duct system
(Fig 5A).
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| Fig 5.
(A) Expression of Fanca at the P0 stage in (A)
the epithelial cells of the developing collecting ducts of the kidney
and (B) the developing tooth. Higher level of expression is noted in
odontoblasts (o) than ameloblasts (a). (C) Expression of Fanca
in the hindlimb at E13.5 predominantly in mesenchymal cells (m) rather
than in precartilage cells (p). Controls are shown as indicated in Fig
2.
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Tooth development occurs through an interaction between the epithelium
of the first arch and the underlying ectomesenchyme derived from the
neural crest.30 During the perinatal stage the epithelium
differentiates into enamel-secreting ameloblasts, whereas the
ectomesenchymal cells become the dentin-secreting odontoblasts.
Although both cell types contained Fanca transcripts, higher
levels were detected in ameloblasts (Fig 5B).
Forelimb buds are first observed at E9.5, whereas hindlimb buds can be
observed soon after E10. Cartilage elements begin to form by E12, and
by E13.3 mesenchymal cells surround the precartilage localized at the
center of each skeletal element. Cartilage is then replaced by bone,
and the mesenchymal cells form the muscles and other soft
tissues.31 At E13.5, Fanca is expressed in the mesenchymal cells of both the forelimb (data not shown) and hindlimb (Fig 5C), but not in the precartilage.
A composite photomicrograph of multiple sections from an E13.5 embryo
is shown (Fig 6). In addition to the
structures discussed above, some Fanca expression is observed
in the heart, but expression in most other tissues, including the
developing gut and lung, was very low or negative when individual
panels of the composite figure were compared with each other. Finally,
there was diffuse but no localized expression at E11.5, including
expression in the neural tube (data not shown).
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| Fig 6.
Global expression of Fanca at E13.5 of mouse
development. Reconstruction image of a whole embryo at E13.5 from
multiple sections visualized with (A) antisense and (A') sense
probes. F, forebrain; H, heart; L, liver; Lu, lung; M, midbrain; S,
stomach.
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DISCUSSION |
Despite the well-established genetic classification of FA into distinct
complementation groups5,6 and the identification of
molecular etiologies for three subgroups,7-10 the
pathogenetic processes involved in this disorder remain obscure.
Studies of protein interaction between FANCA and FANCC have yielded
conflicting results,4,15 and any epistatic relationship
among the FA genes remains speculative. In this context, an
understanding of the expression pattern of Fanca and a
comparison with the known pattern of Fancc can be instructive.
Here we show that the expression of the mouse Fanca gene
exhibits tissue-specific and stage-specific regulation during development.
Fanca expression was observed in multiple tissues, including
the developing placode and dermal papilla that make up the whiskers and
the appendicular skeleton. Expression was noted primarily in cells of
mesenchymal origin that give rise to the soft tissues of the forelimb
and hindlimb. Such mesenchymal derivatives with osteogenic and
hematopoietic potential also contain Fancc
transcripts.20,21 Thus, there is concordance between the
expression patterns of these two FA genes in mesenchymal derivatives.
In addition, Fanca expression was noted in the developing
kidney, liver, and brain, indicating a concordance of expression in
these tissues as well.20 The expression of Fanca in
the brain is particularly noteworthy due to its association with the
intermediate zone, which contains migrating neurons that give rise to
the cerebral cortex. In this compartment, Fanca may be a useful
marker of neuronal migration.
Although many of these findings were reminiscent of the developmental
expression pattern of Fancc,20 there were also
several tissues that showed seemingly discordant patterns of
expression. For example, we found little if any Fanca
expression in the developing lung and gut, organs that were previously
identified to contain Fancc transcripts.20 These
observations suggest that the expression of Fanca is not
necessarily coupled to Fancc during development. In yet other
tissues, comparisons between Fanca and Fancc expression were less clear. Fanca was clearly expressed in two cell types that contribute to tooth formation. Although Fancc expression was previously noted in the developing maxilla, the authors did not
comment on its expression in the developing teeth.20 A
uniform pattern of Fancc expression was also reported
previously in many adult tissues, including testes,21 but
the pattern of expression in the developing gonads was not
stated.20 In the present study, we found little if any
specific hybridization in the developing gonads, including the E13.5
and E16 stages. This is somewhat difficult to reconcile with the
prevalence of infertility and gonadal abnormalities observed in human
patients, features that were also observed in mice nullizygous for
Fancc mutations.32,33 It may suggest that the
gonadal failure is related to hormonal, structural, or other abnormalities rather than to a specific requirement for FA gene products in gonadal tissues.
Beyond the most obvious qualitative differences, however, such
comparisons should be made with caution. In situ hybridization is not a
quantitative test, and subjective interpretations may account for
potential differences between different studies. Also, the analysis of
different tissues and stages was less than exhaustive in both cases,
and low-levels of expression in some tissues may have been overlooked.
Indeed, Fanca expression appeared to be low in most developing
tissues. A further lowering of expression in certain tissues, such as
the gonads, may place them below the limit of detection by in situ
hybridization. Another confounding variable may be the presence of
alternatively spliced transcripts that cannot be detected by certain
probes. Although it is possible that the probe used in our study cannot
detect potential isoforms of Fanca, we believe that this probe
is capable of detecting the major Fanca transcript that encodes
functional Fanca protein. The relatively large size of the probe
spanning eight coding exons, the inability of a longer probe spanning
exons 23-43 to detect additional isoforms by high stringency Northern
hybridization, and the colinearity of the mouse cDNA sequence with the
sequence of the functional human orthologue (data not shown) support
this view. Nevertheless, we cannot exclude the presence of additional Fanca-derived transcripts that may encode functional polypeptides.
Taken together, these results show that Fanca expression occurs
primarily in tissues of epithelial and mesenchymal origin. Defects in
all of these tissues have been implicated in FA patients, confirming
again the pleiotropic nature of FA mutations. However, although there
are certain similarities in the expression patterns of Fanca
and Fancc, there also appear to be distinct domains of expression for each gene during development. At present it is not
possible to deduce the complementation group of FA patients on the
basis of their clinical or cellular phenotype. The difference in the
patterns of expression may provide a useful framework to future studies
that attempt to refine genotype-phenotype correlations in FA. Finally,
the tissue-specific temporal expression of Fanca during
embryogenesis indicates that Fanca-mediated processes are developmentally regulated. We do not yet know the signals that can
induce or repress Fanca transcription in these tissues. The 5' noncoding region of the human FANCA gene is GC-rich
and lacks obvious TATA or CAAT sequences,23 suggesting a
"housekeeping" role for this gene. This region has not yet been
formally tested for promoter activity. It is possible that low levels
of Fanca protein could have a housekeeping function in most tissues,
whereas higher levels may be required in some tissues during
development at certain stages of development. Whether or not this
putative promoter contains the elements necessary for tissue- and
stage-specific expression remains to be determined.
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FOOTNOTES |
Submitted December 1, 1998; accepted March 15, 1999.
Supported by grants from the National Institutes of Health (HL52138)
and the March-of-Dimes Birth Defects Foundation.
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 correspondence to Hagop Youssoufian, MD, Department of
Molecular and Human Genetics, Baylor College of Medicine, One Baylor
Plaza, Houston, TX 77030; email: hagopy{at}bcm.tmc.edu.
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Blood
88:49, 1996[Abstract/Free Full Text]
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