1 Division of Pulmonary Biology, 2 Graduate Program for Molecular and Developmental Biology, and 3 Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Regulation of the surfactant protein B gene (SP-B) is developmentally controlled and highly tissue specific. To elucidate the SP-B gene temporal/spatial expression pattern in lung development at the transcriptional level, a transgenic mouse model line carrying the human SP-B (hSP-B) 1.5-kb 5'-flanking regulatory region and the lacZ gene was established. Expression of hSP-B 1.5-kb lacZ gene started at the onset of lung formation [embryonic day 9 (E9)] and was restricted to epithelial cells throughout prenatal and postnatal lung development. In the adult lung, hSP-B 1.5-kb lacZ gene expression was restricted to bronchiolar and alveolar type II epithelial cells. In lung explant culturing studies, the hSP-B 1.5-kb lacZ gene was highly expressed in newly formed epithelial tubules during the respiratory branching process. In a second transgenic mouse line, an enhancer region, which binds to thyroid transcription factor-1, retinoic acid receptor, signal transducers and activators of transcription 3, and nuclear receptor coactivators (SRC-1, ACTR, TIF2, and CBP/p300), was deleted from the hSP-B 1.5-kb lacZ gene. The deletion abolished hSP-B lacZ gene expression in bronchiolar epithelial cells and significantly reduced its expression level in alveolar type II epithelial cells in transgenic mice.
lung development; thyroid transcription factor-1; retinoic acid receptor; signal transducers and activators of transcription 3; human surfactant protein B; lung branching morphogenesis; lung explant; alveolar type II
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
LUNG DEVELOPMENT CAN BE DIVIDED into prenatal and postnatal stages. Before birth, the primitive lung originates as a diverticulum from the foregut to form a small epithelial tubule surrounded by mesenchymal cells. Through interaction with mesenchymal cells, lung epithelium undergoes multiplication of branches and subsequently forms airways and alveoli. After birth, maturation of the lung continues, entering the alveolarization stage. The alveolarization period starts from the late embryonic period to the neonatal period, accompanied with secretion of pulmonary surfactant primarily by nonciliated bronchiolar epithelial cells (Clara cells) and alveolar type II epithelial cells.
Among surfactant proteins, surfactant protein B (SP-B) is a 79-amino acid amphipathic peptide, produced by the proteolytic cleavage of SP-B proprotein in Clara cells and alveolar type II epithelial cells. The SP-B peptide is stored in lamellar bodies and secreted with phospholipids into the airway lumen. The most renowned function of SP-B is to facilitate the stability and rapid spreading of surfactant phospholipids during the respiratory cycle (16). Null mutations in the SP-B gene caused lethal respiratory distress in newborn infants and in SP-B-deficient mice produced by gene targeting (2, 9). Therefore, SP-B is essential for postnatal lung development, alveolar maturation, and postnatal respiratory adaptation in newborns.
Expression of the SP-B gene is highly tissue specific and
developmentally controlled. In the adult lung, expression of SP-B is
restricted to Clara cells and alveolar type II epithelial cells. The
control of human SP-B (hSP-B) gene expression is determined by
cis-acting DNA elements and trans-acting
transcription factors. Through in vitro study, an important enhancer
region has been located at 500 to
331 bp from the transcriptional
starting site of the hSP-B gene in respiratory epithelial cells
(19). Multiple transcription factors and
coactivators have been identified to form an enhanceosome on the
enhancer, including thyroid transcription factor-1 (TTF-1), retinoic
acid receptor (RAR), nuclear receptor coactivators (p160 coactivators
and CBP/p300), and signal transducers and activators of transcription 3 (STAT3) (7, 8, 17, 18). These factors strongly stimulate
hSP-B gene transcription in respiratory epithelial cells in a
synergistic manner. TTF-1 is a homeodomain containing tissue-specific
transcription factor of Nkx2 family members. In the lung, TTF-1 is
present at the earliest stages of differentiation of epithelium and is
later confined to respiratory epithelial cells (3, 8, 12,
21). In TTF-1
/
mice, lung branching morphogenesis is
severely disrupted (11). RAR signaling is also required
for lung organogenesis. RAR-
/
and RAR-
/
double knockout
mice develop lung hypoplasia and aplasia (6). In addition,
retinoic acid is a stimulatory reagent for alveolarization and
realveolarization after lung injury (4, 5). STAT3 can be
activated by a number of cytokines and growth factors, including
interleukin (IL)-6 family cytokines and epidermal growth factor
(20). IL-6 and IL-11 strongly stimulate SP-B gene expression in the mouse lung (18). Unlike in other
STAT-deficient mice that are born alive, targeted disruption of the
mouse STAT3 gene leads to early embryonic lethality (14),
indicating that it is involved in normal embryonic development.
On the basis of in vitro characterization, we hypothesize that
TTF-1, RAR/retinoid X receptor (RXR), nuclear receptor coactivators, and STAT3 on the enhancer (500 to
375 bp) determine in vivo temporal/spatial expression of the hSP-B gene in the lung. Unlike the
in vitro systems, in vivo SP-B gene expression in lung development is
largely dependent on multicellular interactions, especially mesenchymal-epithelial cell interactions. In this report, a transgenic mouse system containing the hSP-B 1.5-kb 5'-flanking regulatory region
and the lacZ reporter gene was established to systematically study the hSP-B gene temporal/spatial expression pattern during lung
development. In addition, a second transgenic mouse line containing
enhancer deletion in the hSP-B 1.5-kb lacZ gene was also
established to elucidate the functional role of the enhancer in hSP-B
temporal/spatial expression.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Antibody immunohistochemistry. The lungs from wild-type FVB/N adult mice were infused with a fixative solution (4% paraformaldehyde, 1× PBS) via the trachea, dissected out, and stored in fixative at 4°C for ~24 h. For postnatal lung day 1 and day 4, lungs were dissected out for fixation. For prenatal animals, embryos were dissected out for fixation. After being fixated and embedded in paraffin, embryos and lung tissue sections were cut 5 µm thick. The slides were baked at 60°C for 2 h and washed in a series of xylene and ethanol to remove paraffin from the tissues. Endogenous peroxidase activity was removed from tissues by incubating the tissue slides in methanol and hydrogen peroxide for 15 min. Tissue slides were incubated overnight at 4°C with a primary SP-B protein polyclonal antibody (1:1,000-1:2,000). The antibody was provided by the Morphology Core Facility of the Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center (see Ref. 21). Preimmune serum was added in the negative control. The tissues were washed and treated with secondary conjugated antibodies 24 h later. The interactions were amplified with Vectastain Elite ABC kit to visualize the signals.
Construction of the wild-type and deletion mutant hSP-B 1.5-kb
lacZ/pSV--galactosidase reporter gene vectors.
The hSP-B 1.5-kb lacZ expression vector was made by
subcloning the hSP-B 1.5-kb 5'-flanking regulatory region into the
pSV-
-galactosidase (
-gal) vector (Promega) at the
EcoRI/ HindIII sites using a PCR strategy as
previously described (19). The hSP-B 1.5-kb enhancer deletion mutation was made by removal of the
550- to
351-bp region
using the double PCR strategy and subcloning into the pSV-
-gal vector at the EcoRI/HindIII sites as previously
described (19).
H441 cell culture and transient transfection.
H441 cells were cultured in RPMI supplemented with 10% fetal
calf serum, glutamine, and penicillin/streptomycin. Cells were maintained and passaged weekly at 37°C in 5% CO2-air.
H441 cells were seeded at a density of 2 × 105
cells/well in six-well plates. The hSP-B 1.5-kb lacZ
reporter and control constructs (0.25 µg) were transfected into H441
cells by Fugene6 (Boehringer Mannheim). After 72 h, cells were
fixed for immunohistochemical -gal staining.
Generation of transgenic mice.
The expression cassette containing the hSP-B 1.5-kb 5'-flanking
regulatory region (or hSP-B 1.5-kb with deletion of the 550- to
351-bp region), the lacZ gene, and the simian virus
40 small T antigen poly(A) signals was dissected out, purified,
and sent to the Transgenic Core Facility of the University of
Cincinnati for microinjection. Founders were identified by PCR using a
pair of primers spanning from the hSP-B promoter to the lacZ gene.
Immunohistochemistry of -gal staining.
For adult lungs and postnatal day 10 and day 15 lungs, whole lungs were prefixed with a fix solution (0.4 ml 25%
glutaraldehyde, 1.0 ml 250 mM EGTA, 5.0 ml 1 M MgCl2, and
43.5 ml PBS) on ice for 4 h, followed by three washes (15 min
each) in a wash buffer containing 1.0 ml 1 M MgCl2, 5.0 ml
2% sodium deoxycholate, 5.0 ml 2% Nonidet P-40, and 489 ml 100 mM
sodium phosphate buffer, pH 7.3. Subsequently, lungs were stained with
LacZ solution (48 ml wash buffer, 2 ml 25 mg/ml X-gal, 0.106 g
potassium ferrocyanide, and 0.042 g potassium ferricyanide)
overnight at room temperature. The next day, lungs were rinsed three
times (10 min each) with PBS and fixed in a postfixative solution (3.2 ml 25% glutaraldehyde, 5 ml 16% paraformaldehyde, 4 ml 1 M sodium
cacodylate, and 27.8 ml water) for 10 min. Lungs were dehydrated
through a graded series of ethanol washes. After being fixated and
embedded in paraffin, embryos and lung tissue sections were cut 5 µm
thick. The slides were baked at 60°C for 2 h and washed in a
series of xylene and ethanol to remove paraffin from the tissues. For
prenatal lungs and postnatal lungs day 1 and day
4, cryostat sections of frozen embryos or lung tissues were used
for
-gal staining. H441 cell
-gal staining was performed
essentially the same.
Assay of -gal activity.
Various tissues were collected from both wild-type and transgenic FVB/N
adult mice for homogenization in PBS. Approximately 1 ng of protein was
used for
-gal assay as described previously (19). For
cultured alveolar type II epithelial cells, cells were lysed in
reporter lysis buffer for luciferase assay (Promega) and subsequently
used for
-gal assay.
Lung explant culture and -gal staining.
Lung buds were dissected out from embryonic day 12 (E12)
embryos of nontransgenic wild-type or hSP-B 1.5-kb lacZ gene
transgenic mice. The buds were cultured on top of 1% low melting point
agarose gel in DMEM/F-12 with supplementation of 10% fetal calf serum in a 30-mm dish. The next day, a final concentration of 0.2 mg/ml of
X-gal was added to the culture medium and incubated for 2 more days.
The cultured lung explants were changed with fresh medium each day.
Alveolar type II cell purification and culturing. The study was performed essentially the same as previously described (10). Two-mo-old mice were anesthetized by intraperitoneal injection. The abdominal cavity was opened, and mice were exsanguinated by severing the inferior vena cava and the left renal artery. The trachea was isolated and cannulated with a 20-gauge luer stub adapter. The diaphragm was cut, and the chest plate and thymus were removed. With the use of a 21-gauge needle fitted on a 10-cc syringe, lungs were perfused with 10-20 ml of 0.9% saline via the pulmonary artery. Three milliliters of dispase were rapidly instilled through the cannula in the trachea, followed by 0.5 ml of agarose (45°C). Lungs were immediately covered with ice for 2 min to gel the agarose. After this incubation, lungs were removed from the animals and incubated in 1 ml of dispase for 45 min (25°C). Lungs were subsequently transferred to a 60-mm culture dish containing 7 ml of HEPES-buffered DMEM and 100 U/ml of DNase I, and lung tissue was gently teased from the bronchi. The cell suspension was filtered through progressively smaller cell strainers (100 µm, 40 µm) and nylon gauze (20 µm). Cells were collected by centrifugation at 130 g for 8 min (4°C) and placed on prewashed 100-mm tissue culture plates coated for 24-48 h at 4°C with 42 µg of CD45 and 16 µg of CD32 in 1× PBS. After being incubated for 1-2 h at 37°C, type II cells were gently panned from the plate and collected by centrifugation. Monolayers of type II cells were cultured on Matrigel-rat tail collagen (70:30, vol/vol) in bronchial epithelial cell basal medium (minus hydrocortisone) plus 5% charcoal-stripped fetal bovine serum and 10 ng/ml of keratinocyte growth factor. The media were changed after the first day of culture and every 2 days thereafter. For cell harvest, matrices were solubilized by incubating cultures with dispase containing 1 mg/ml of collagenase at 37°C for 60 min.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Temporal/spatial expression of endogenous SP-B in postnatal lungs.
Cell type-specific expression of the endogenous SP-B was assessed using
antibody against the SP-B protein by immunohistochemical staining. In
the neonatal lungs, SP-B expression was detected in developing
epithelial cells and later was restricted to Clara cells and
alveolar type II epithelial cells in the adult lungs (Fig.
1). SP-B expression correlates with lung
alveolar maturation. This result was in agreement with previous
findings (21). In the negative control using preimmune
antiserum, no specific staining was detected in the lung (data not
shown).
|
Generation of the hSP-B 1.5-kb lacZ transgenic mouse line.
To assess whether SP-B cell type-specific expression is controlled by
the 5'-flanking sequence at the transcriptional level during lung
development, an expression cassette containing the hSP-B 1.5-kb
5'-flanking regulatory region and the lacZ gene was constructed. To test lacZ gene expression, the hSP-B 1.5-kb
lacZ gene construct was transfected into H441 cells. With
the use of -gal staining, expression of the lacZ gene was
detected in H441 cells (data not shown). Next, the DNA fragment
containing the hSP-B 1.5-kb lacZ gene expression cassette
was microinjected into the mouse to establish founder lines. The
positively genotyped lungs were inflated and dissected out for
-gal
staining. As shown in Fig. 2, the adult
lung from transgenic mice showed lacZ gene expression by
-gal staining (blue color). As control, the nontransgenic wild-type lung showed no
-gal activity.
|
Tissue and cell type-specific expression of the hSP-B 1.5-kb lacZ
gene in transgenic animals.
To examine tissue expression of the hSP-B 1.5-kb lacZ gene,
various organs were collected from wild-type and transgenic animals for
-gal assay. Only the transgenic lungs and the intestines demonstrated
-gal activity (Fig. 3).
To further identify cell type expression of the hSP-B 1.5-kb
lacZ gene in each organ, adult tissue sections were prepared
from various organs of the transgenic animals. Again, only lung and
intestine tissue sections showed
-gal staining (Fig.
4). In the adult lung,
-gal staining
was restricted to bronchiolar and alveolar type II epithelial cells, identical to endogenous SP-B expression, indicating that SP-B tissue
and cell type-specific expression are controlled by this hSP-B 1.5-kb
genetic sequence. There was no detectable
-gal staining in the
nontransgenic lungs, except some weak endogenous staining in
respiratory macrophages. In the intestines,
-gal staining was
detected and restricted to goblet cells along the villi and Paneth
cells. The hSP-B 1.5-kb lacZ gene expression in the
intestines appears not to be affected by the position of DNA random
insertion, because at least three transgenic founders showed intestinal
expression of the hSP-B 1.5-kb lacZ gene. No specific
staining was detectable in the nontransgenic intestines (data not
shown).
|
|
Temporal/spatial expression of the hSP-B 1.5-kb lacZ gene in the
developing lungs.
To further assess the temporal/spatial expression pattern of the hSP-B
gene in developing lungs, -gal staining of hSP-B 1.5-kb lacZ gene expression was systematically analyzed during lung
development. First, embryonic tissues from various developing stages
were collected and stained for
-gal activity. The staining of
-gal activity was detected in respiratory epithelial cells at as
early as E9, the onset of lung formation when only one epithelial
tubule was formed (Fig. 5). Throughout
lung development, hSP-B 1.5-kb lacZ gene expression was
continuously detected in and highly restricted to developing epithelial
tubules.
|
|
Expression of the hSP-B 1.5-kb lacZ gene in branching morphogenesis
of cultured lung explants.
To study whether expression of the hSP-B 1.5-kb lacZ gene is
associated with respiratory branching morphogenesis, lung buds from E12
day embryos were dissected out and cultured in vitro in the presence of
X-gal. After 2 days of incubation, -gal activity was highly
integrated into the newly branched epithelial tubules (Fig.
7). There was faint staining in the lung
explants isolated from nontransgenic animals in the cultured
conditions.
|
The enhancer 550 to
351 bp
determines hSP-B gene expression in bronchiolar epithelial cells.
As discussed earlier, a series of in vitro studies identified an
important enhancer region on the hSP-B gene, which binds to multiple
trans-acting factors that form an enhanceosome. To identify
the functional role of this enhancer in hSP-B temporal/spatial expression in the lung, a lacZ transgenic mouse line
containing an hSP-B 1.5-kb deletion mutation that lacks the enhancer
region was made (Fig. 8A). The
transcriptional activity of the deletion construct had been tested in
H441 cells that showed much lower
-gal activity compared with the
wild-type hSP-B 1.5-kb lacZ construct (data not shown).
Analysis of this transgenic mouse line revealed that there was no
lacZ gene expression in bronchiolar epithelial cells (Fig.
8B). Therefore, the enhancer is essential for hSP-B gene
expression in bronchiolar epithelial cells. Although
-gal activity
could be detected in alveolar type II epithelial cells, the expression
level was dramatically reduced (Fig. 8B). To quantitatively compare expression levels between the wild-type hSP-B 1.5-kb
lacZ gene and the enhancer deletion mutant mice, alveolar
type II epithelial cells were purified from both transgenic lines and
cultured in vitro for
-gal assay. The
-gal activity comparison
indicated that removal of the enhancer region resulted in ~70%
-gal activity reduction in cultured alveolar type II epithelial
cells (Fig. 8C).
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In contrast to other surfactant protein (SP-A, SP-C, and SP-D)-deficient mice that are born alive, targeted disruption of the mouse SP-B gene leads to lethality of newborn mice (2), suggesting that SP-B is essential for postnatal lung function. It appears that SP-B gene activation starts at the onset of lung development, since expression of the hSP-B 1.5-kb lacZ reporter gene could be detected at E9 of embryonic lung development (Fig. 5), a stage with only one epithelial tubule present. After fetal lung development, the hSP-B 1.5-kb lacZ gene was continuously expressed in branching epithelial tubules in animals (Figs. 5 and 6) and in in vitro lung explants (Fig. 7), suggesting transcription of the hSP-B gene was activated throughout respiratory epithelial differentiation and proliferation during lung development. This process recapitulates endogenous mouse SP-B expression and agrees with the observation made by others using the chloramphenicol acetyltransferase as a reporter gene (13).
The observation made in this report suggests that the 1.5-kb
5'-flanking regulatory region of the hSP-B gene contains sufficient positive cis-acting genetic sequences required for tissue
and cell type-specific expression in the developing and mature mouse lungs. The observation suggests that common genetic sequences and
mechanisms control both human and mouse SP-B gene regulation during
lung development. One of the common sequences shared by human and mouse
is the enhancer region located in 500 to
331 bp of the hSP-B
5'-flanking regulatory region (19). The enhancer region
binds to multiple transcription factors (including TTF-1, RAR/RXR,
STAT3) and nuclear receptor coactivators (CBP, SRC-1, ACTR, TIF2) with
intrinsic histone acetyltransferase activity that form an enhanceosome
(7, 8). These factors mediate retinoic acid and
IL-6 family cytokine stimulation of the hSP-B gene in respiratory
epithelial cells (7, 8, 17, 18). Among them, TTF-1 is a
tissue-specific transcription factor and plays a central role in
enhanceosome complex formation (3, 7, 8, 19, 21).
Importantly and interestingly, the temporal/spatial expression pattern
of TTF-1 (8, 21) matches very well with the hSP-B 1.5-kb
lacZ gene expression pattern in both developing and mature
lungs (Figs. 4-6). It has been shown that TTF-1 is a strong
transcription activator for SP-B gene expression and lung branching
morphogenesis in respiratory epithelial cells (1, 11, 15,
19). TTF-1 can interact with RAR, nuclear receptor coactivators,
and STAT3 to regulate hSP-B gene expression in mediating retinoic acid
signaling and IL-6 family cytokine signaling (7, 8, 17,
18). These factors interact with each other on the enhancer as
identified by mammalian two-hybrid assay, glutathione S-transferase pull down assay, chromatin immunoprecipitation
assay, and confocal microscope colocalization assay (7, 8, 17, 18). These factors plus other unidentified factors on
the enhancer exercise a combinatorial effect to control
temporal/spatial expression of the SP-B gene in the lung. In this
report, after deletion of the enhancer region, the hSP-B 1.5-kb
lacZ gene was no longer expressed in bronchiolar epithelial
cells of the transgenic mouse. Therefore, the enhancer region and
associated trans-acting factors are essential for hSP-B gene
expression in bronchiolar epithelial cells. The study indicates that
cell type-specific expression of the hSP-B gene in bronchiolar and
alveolar type II epithelial cells is controlled by different sets of
genetic elements and transcription factors. It remains to be determined
which region(s) within the hSP-B 1.5-kb 5'-flanking regulatory region
controls alveolar type II epithelial cell expression, although deletion of the enhancer substantially reduced lacZ reporter gene
expression in these cells (Fig. 8C).
In addition to the lung, expression of the hSP-B 1.5-kb lacZ
gene was also observed in adult intestinal epithelial cells (goblet and
Paneth cells) of transgenic mice (Fig. 4). Weak -gal expression has
also been observed in trachea (goblet cells) and thyroid (data not
shown). Other researchers have also made the same observation using the
chloramphenicol acetyltransferase reporter gene (13). This
raises a very interesting issue. It suggests that some negative sequences beyond the hSP-B 1.5-kb 5'-flanking regulatory region are
important contributors for tissue-specific expression of the SP-B gene.
The sequences appear to suppress hSP-B gene transcription in the
intestine, trachea, and thyroid. In addition, detection of hSP-B 1.5-kb
lacZ gene expression in the intestine and thyroid implies
that these organs originate from the same progenitor cells as the lung.
Similar to the lung, intestine development starts at a rather late
embryonic stage. Both organs have an internal interface to separate the
body from the outside environment, and both organs are repeatedly
exposed to external microorganisms and pathogens. In addition to
serving as barriers, both organs actively participate in host defense
through cytokine- and chemokine-mediated inflammatory responses. The
enhancer deletion mutant of the hSP-B 1.5-kb lacZ gene
transgenic mice still retained low
-gal activity in the intestine
(data not shown), suggesting that the enhancer is required for
lung-specific activity in bronchiolar epithelial cells.
In summary, generation of the hSP-B 1.5-kb lacZ gene and
enhancer deletion mutant transgenic mice reveals the temporal/spatial expression pattern of hSP-B transcription in vivo, suggesting that both
positive and negative DNA regulatory sequences contribute to hSP-B gene
tissue and cell type-specific expression. The studies demonstrate that
the enhancer region (550 to
351 bp) and its associated
trans-acting factors have at least two functions in vivo:
1) to determine bronchiolar epithelial cell-specific
expression and 2) to elevate SP-B gene basal level
expression in alveolar type II epithelial cells. The studies have
identified a correlation between SP-B transcription and lung epithelial
cell differentiation, proliferation, and alveolar maturation. Our
findings support the concept that SP-B is critical for postnatal lung
development and the pulmonary surfactant structure. These transgenic
mouse lines will provide useful tools for characterization of
cis-acting elements and transcription factors that control
SP-B transcription in vivo. They can serve as markers for studying
respiratory epithelial cell differentiation, proliferation, and
regeneration during prenatal and postnatal lung development.
![]() |
ACKNOWLEDGEMENTS |
---|
We thank Drs. Tim Weaver, Jeffrey A. Whitsett, Susan Wert, and Michael Crossman for useful discussions. We thank Yume Ray for technical help in alveolar type II epithelial cell isolation and culturing and Huajin Wen for technical help in lung explant culturing.
![]() |
FOOTNOTES |
---|
This work was supported by National Institutes of Health (NIH) Grant HL-61803 (C. Yan), an American Lung Association grant (C. Yan), March of Dimes Grant FY02-206 (C. Yan), and NIH Grant DK-54930 (H. Du).
Address for reprint requests and other correspondence: C. Yan, Children's Hospital Medical Center, Division of Pulmonary Biology, TCHRF, 3333 Burnet Ave., Cincinnati, OH 45229-3039 (E-mail Cong.Yan{at}chmcc.org).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajplung.00280.2002
Received 14 August 2002; accepted in final form 25 October 2002.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Bohinski, RJ,
Di Lauro R,
and
Whitsett JA.
The lung-specific surfactant protein B gene promoter is a target for thyroid transcription factor 1 and hepatocyte nuclear factor 3, indicating common factors for organ-specific gene expression along the foregut axis.
Mol Cell Biol
14:
5671-5681,
1994[Abstract].
2.
Clark, JC,
Wert SE,
Bachurski CJ,
Stahlman MT,
Stripp BR,
Weaver TE,
and
Whitsett JA.
Targeted disruption of the surfactant protein B gene disrupts surfactant homeostasis, causing respiratory failure in newborn mice.
Proc Natl Acad Sci USA
92:
7794-7798,
1995[Abstract].
3.
Lazzaro, D,
Price M,
de Felice M,
and
Di Lauro R.
The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain.
Development
113:
1093-1094,
1991[Abstract].
4.
Massaro, GD,
and
Massaro D.
Postnatal treatment with retinoic acid increases the number of pulmonary alveoli in rats.
Am J Physiol Lung Cell Mol Physiol
270:
L305-L310,
1996
5.
Massaro, GD,
and
Massaro D.
Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats.
Nat Med
3:
675-677,
1997[ISI][Medline]. [Corrigenda. Nat Med 3: July 1997, p. 805.]
6.
Mendelsohn, C,
Lohnes D,
Decimo D,
Lufkin T,
LeMeur M,
Chambon P,
and
Mark M.
Function of the retinoic acid receptors (RARs) during development. II. Multiple abnormalities at various stages of organogenesis in RAR double mutants.
Development
120:
2749-2771,
1994
7.
Naltner, A,
Ghaffari M,
Whitsett JA,
and
Yan C.
Retinoic acid stimulation of the human surfactant protein B promoter is thyroid transcription factor 1 site-dependent.
J Biol Chem
275:
56-62,
2000
8.
Naltner, A,
Wert S,
Whitsett JA,
and
Yan C.
Temporal/spatial expression of nuclear receptor coactivators in the mouse lung.
Am J Physiol Lung Cell Mol Physiol
279:
L1066-L1074,
2000
9.
Nogee, LM,
Garnier G,
Dietz HC,
Singer L,
Murphy AM,
deMello DE,
and
Colten HR.
A mutation in the surfactant protein B gene responsible for fatal neonatal respiratory disease in multiple kindreds.
J Clin Invest
93:
1860-1863,
1994[ISI][Medline].
10.
Rice, WR,
Conkright JJ,
Na CL,
Ikegami M,
Shannon JM,
and
Weaver TE.
Maintenance of the mouse type II cell phenotype in vitro.
Am J Physiol Lung Cell Mol Physiol
283:
L256-L264,
2002
11.
Kimura, S,
Hara Y,
Pineau T,
Fernandez-Salguero P,
Fox CH,
Ward JM,
and
Gonzalez FJ.
The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary.
Genes Dev
10:
60-69,
1996[Abstract].
12.
Stahlman, MT,
Gray ME,
and
Whitsett JA.
Expression of thyroid transcription factor-1 (TTF-1) in fetal and neonatal human lung.
J Histochem Cytochem
44:
673-678,
1996
13.
Strayer, M,
Savani RC,
Gonzales LW,
Zaman A,
Cui Z,
Veszelovszky E,
Wood E,
Ho YS,
and
Ballard PL.
Human surfactant protein B promoter in transgenic mice: temporal, spatial, and stimulus-responsive regulation.
Am J Physiol Lung Cell Mol Physiol
282:
L394-L404,
2002
14.
Takeda, K,
Noguchi K,
Shi W,
Tanaka T,
Matsumoto M,
Yoshida N,
Kishimoto T,
and
Akira S.
Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality.
Proc Natl Acad Sci USA
94:
3801-3804,
1997
15.
Venkatesh, VC,
Planer BC,
Schwartz M,
Vanderbilt JN,
White RT,
and
Ballard PL.
Characterization of the promoter of human pulmonary surfactant protein B gene.
Am J Physiol Lung Cell Mol Physiol
268:
L674-L682,
1995
16.
Whitsett, JA,
Nogee LM,
Weaver TE,
and
Horowitz AD.
Human surfactant protein B: structure, function, regulation, and genetic disease.
Physiol Rev
75:
749-757,
1995
17.
Yan, C,
Naltner A,
Conkright J,
and
Ghaffari M.
Protein-protein interaction of retinoic acid receptor- and thyroid transcription factor-1 in respiratory epithelial cells.
J Biol Chem
276:
21686-21691,
2001
18.
Yan, C,
Naltner A,
Martin M,
Naltner M,
Fangman JM,
and
Gurel O.
Transcriptional stimulation of the surfactant protein B gene by STAT3 in respiratory epithelial cells.
J Biol Chem
11:
11,
2002.
19.
Yan, C,
Sever Z,
and
Whitsett JA.
Upstream enhancer activity in the human surfactant protein B gene is mediated by thyroid transcription factor 1.
J Biol Chem
270:
24852-24857,
1995
20.
Zhong, Z,
Wen Z,
and
Darnell JE, Jr.
Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6.
Science
264:
95-98,
1994[ISI][Medline].
21.
Zhou, L,
Lim L,
Costa RH,
and
Whitsett JA.
Thyroid transcription factor-1, hepatocyte nuclear factor-3, surfactant protein B, C, and Clara cell secretory protein in developing mouse lung.
J Histochem Cytochem
44:
1183-1193,
1996