Programs in 1 Cell Biology and 2 Pathology, The Hospital for Sick Children, and Biochemistry Department, University of Toronto, Toronto, Ontario, Canada M5G 1X8
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ABSTRACT |
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Protein tyrosine phosphatase-
(PTP-
) is a member of the mammalian LAR family of phosphatases,
which is characterized by a cell adhesion-like ectodomain, a single
transmembrane segment, and two tandemly repeated intracellular
catalytic domains. The expression of PTP-
is developmentally
regulated in epithelial, neuronal, and neuroendocrine tissues. We
previously showed that PTP-
is strongly expressed within the fetal,
but not adult, rat lung and is localized to the Clara cells and type II
pneumocytes. In view of the developmentally regulated pulmonary
expression of PTP-
, we performed a detailed histological and
ultrastructural study of the lungs of PTP-
knockout mice we have
generated. Our findings indicate no apparent structural abnormalities
in the lungs of PTP-
/
mice, including airway and
alveolar epithelium. In addition, pulmonary neuroendocrine cells also
appear normal, in contrast to pituitary, pancreatic, and
gastrointestinal endocrine cells, in the knockout mice, suggesting
different developmental regulation of these neuroendocrine cells. These
observations suggest compensation for the absence of PTP-
during
development by related family member phosphatases, such as LAR.
pulmonary; knockout mice; neuroepithelial body
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INTRODUCTION |
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PROTEIN TYROSINE
PHOSPHATASE (PTP)- is a transmembrane receptor PTP and a
member of the mammalian LAR family, which consists of the three closely
related enzymes: PTP-
, PTP-
, and LAR. PTP-
contains a cell
adhesion molecule (CAM)-like ectodomain, a single transmembrane domain,
and two tandemly repeated intracellular phosphatase domains (13,
19, 22, 25, 27). The proximal phosphatase domain is
catalytically active, whereas the second domain is inactive and serves
a regulatory role (21). The CAM-like ectodomain of PTP-
bears a strong resemblance to the ectodomain of neural CAMs of the Ig
superfamily, such as L1 and N-CAM (3, 6). These molecules
regulate the development of specific axonal projections in the
nervous system. The substrate and ligand for PTP-
and the signaling
networks in which it functions remain unknown.
PTP- expression is tightly controlled and developmentally regulated
within epithelial, neuronal, and neuroendocrine tissues and organs
(13, 15, 23, 25). It plays a critical role in the
development of the pituitary, pancreas, enteroendocrine gut, and
peripheral nerve. PTP-
knockout mice demonstrate pituitary and
pancreatic islet hypoplasia associated with deficiencies of growth
hormone (GH), prolactin, and insulin (1, 4, 20). Severe GH
deficiency contributes to neonatal hypoglycemia in the PTP-
/
mice and a high neonatal mortality rate (60%)
(1). The peripheral nerve in the PTP-
-deficient mice
shows developmental delay (20) and significant
abnormalities of axon guidance and regenerative capacity after injury
(12).
Within the rat lung, PTP- is predominantly and strongly expressed in
proliferating and differentiating epithelial cells (fetal Clara cells
and type II pneumocytes) of the embryonic, fetal, and neonatal airway
and alveolar sacs (9). PTP-
is not found in quiescent
adolescent and adult rat pulmonary epithelium. On the basis of this
cell-specific and developmentally regulated pulmonary expression and
the absolute requirement for PTP-
in the developing nervous and
neuroendocrine systems, we hypothesized that PTP-
would also play a
role in the development of the mammalian respiratory system. We thus
performed detailed histological and ultrastructural assessment of the
lungs in PTP-
-deficient mice.
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MATERIALS AND METHODS |
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The full-length PTP- gene was inactivated, and mice were
characterized as previously described (20). The
PTP-
+/
mice are phenotypically indistinguishable from
PTP-
+/+ mice. The PTP-
/
animals
consisted of three cohorts: most (60%) died as neonates within hours
of birth, 37.5% demonstrated growth retardation and succumbed to a
wasting syndrome by 2-3 wk of age, and 2.5% survived to
adulthood, appeared healthy, and were fertile.
All animal experimentation was conducted in accordance with accepted standards of humane animal care.
Lac Z staining.
The knockout cassette used to generate the PTP- knockout mice
contains the
-galactosidase gene, allowing Lac Z
staining to determine the expression pattern of PTP-
. Animals were
killed, and the lungs were harvested and fixed in 0.1 M sodium
phosphate buffer (pH 7.9) containing 1% formaldehyde, 0.1%
glutaraldehyde, 2 mM MgCl2, and 5 mM EGTA for 6 h.
Organs were washed for 2 h with four exchanges of a wash buffer (2 mM MgCl2, 0.01% deoxycholate, and 0.02% NP-40 in 0.1 M
sodium phosphate buffer, pH 7.9) at room temperature. The tissue was
then incubated in PBS containing 5 mM ferricyanide, 5 mM ferrocyanide,
2 mM MgCl2, and X-gal (Roche; 0.1 mg/ml) overnight at
37°C. Tissues were subsequently rinsed in 70% ethanol, embedded in
paraffin, and sectioned.
Lung wet-to-dry weight ratios.
Newborn litters were killed via decapitation, and the right lung was
immediately excised, gently blotted on a cotton towel, and weighed to
obtain the lung wet weight. The lungs were then placed in a 50°C oven
and weighed daily until a stable dry weight was obtained (72 h).
Wet-to-dry lung weight ratios were determined for
PTP-
/
, PTP-
+/
, and
PTP-
+/+ newborns. An increased ratio is indicative of an
increase in intravascular and/or interstitial lung water content.
Histopathology.
Representative mice from each of the three PTP-/
cohorts and sibling controls were euthanized. Newborn mice were
decapitated, and the lungs were dissected and fixed overnight in 4%
paraformaldehyde at 4°C. Adult and 2- to 3-wk-old mice were sedated
with an intraperitoneal injection of chloral hydrate and subsequently
perfusion fixed with 4% paraformaldehyde. Alternatively, these two
cohorts of mice were euthanized by lethal intraperitoneal injection of
pentobarbital sodium. The lungs were then dissected and fixed overnight
in 10% buffered formalin at 4°C. All lung tissue was subsequently
embedded in paraffin, sectioned (5 µm), and stained with hematoxylin
and eosin (H & E) or periodic acid-Schiff (PAS).
Electron microscopy.
Representative newborn, 2- to 3-wk-old, and adult
PTP-/
mice and appropriate controls were euthanized;
the lungs were dissected and fixed overnight in 1% glutaraldehyde-4%
formaldehyde in 0.1 M phosphate buffer. Lungs were washed once in 0.1 M
phosphate buffer for 5 min and then postfixed in 2% OsO4.
Reduced osmium fixation (2% OsO4 and ferrocyanide) was
used to demonstrate cytoplasmic glycogen. Sections (1 µm) were
dehydrated in graded acetone, embedded in Epon, and stained with
toluidine blue; ultrathin sections were stained with uranyl acetate and
lead citrate. Electron-microscopic examination was performed with a
transmission electron microscope (model 201, Phillips).
Immunohistochemistry.
Immunohistochemical localization of calcitonin gene-related peptide
(CGRP), a marker of neuroepithelial bodies (NEB) in rodent lungs, was
carried out as previously reported (5). Briefly, representative mice from each of the three PTP-/
cohorts were euthanized, and the lungs were dissected and fixed for 30 min (newborn) or 2 h (2-3 wk old and adult) at room
temperature in Bouin's fixative. Lungs were subsequently washed four
times with PBS overnight at 4°C, embedded in paraffin, and sectioned (5 µm). Sections were blocked and incubated with a rabbit polyclonal CGRP antiserum (Chemicon) at a dilution of 1:400 overnight at 4°C,
followed by biotinylated secondary antibody, streptavidin-HRP (Vectastain Elite ABC kit; Vector Labs) and developed in
diaminobenzidine (0.5 mg/ml) and H2O2 (0.03%).
Appropriate positive and negative (omission of primary antibody)
controls were performed.
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RESULTS |
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Developmental expression of PTP- in mouse lungs.
The PTP-
knockout cassette contains the
-galatosidase gene
(20). Lac Z staining was therefore undertaken to localize
the expression of PTP-
within the lungs of the three cohorts of
PTP-
/
, PTP-
+/
, and
PTP-
+/+ mice. PTP-
is expressed within the walls of
the alveolar sacs, airway epithelium, and pulmonary vessels of newborn
mice (Fig. 1, A and
B). At 2-3 wk of age, LacZ staining is evident in the alveolar walls and pulmonary vessels but is no longer expressed in the
airway epithelium (Fig. 1, D and E). As in other
tissues, PTP-
expression decreases dramatically as the animal
matures and is absent from the lungs of the adult mice (Fig. 1,
G and H). These results are in agreement
with our previously observed decline of PTP-
expression with
maturation of rat lung epithelia (9).
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Analysis of pulmonary edema.
During the original phenotypic characterization of the
PTP-/
mice, pulmonary edema was noted in some of the
newborn animals (20). To further investigate this
observation and analyze its prevalence, the lung wet-to-dry weight
ratio was determined for a large series of newborn mice. The presence
of fluid within the lung manifests as an increase in the lung
wet-to-dry weight ratio. Figure 2 shows
no significant difference in the lung wet-to-dry weight ratio between
PTP-
/
, PTP-
+/
, and
PTP-
+/+ newborn mice. This suggests that, overall, there
is no significant pulmonary edema in the PTP-
/
newborn.
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Analysis of lung architecture.
Analysis of H & E-stained sections of lungs from newborn and adult
PTP-/
mice revealed no apparent abnormalities (Fig.
3, A and E).
Specifically, the alveoli and epithelial lining of the bronchioles
appeared normal, and alveolar pulmonary edema was not evident in the
newborn PTP-
/
mice (Fig. 3A). One
18-day-old PTP-
/
mouse (2- to 3-wk-old cohort)
demonstrated significant bronchial epithelial hyperplasia and possibly
metaplasia (data not shown), but similar findings were not evident, and
the lungs appeared normal in the large majority of this cohort (Fig.
3C).
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Pulmonary neuroendocrine cells.
We previously described abnormalities of the neuroendocrine system
(pituitary, pancreas, and enteroendocrine cells of the gut) of the
PTP-/
mice (1, 20). To determine
whether the pulmonary neuroendocrine cell (PNEC) system may be
similarly affected by the loss of PTP-
, we immunostained the lungs
of the PTP-
/
mice for CGRP, a marker of PNEC and NEB
(5). Our findings show that PNEC and NEB in the lungs of
PTP-
/
mice (Fig. 7,
A and B) were comparable to those in the lungs of
PTP-
+/
and PTP-
+/+ sibling control mice
(Fig. 7, C and D).
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DISCUSSION |
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We previously demonstrated by in situ hybridization and Northern
blot analysis that PTP- expression is developmentally regulated in
the rat lung (9, 14). The highest levels of expression of
PTP-
in lungs were evident in fetal and newborn epithelium of the
bronchi, terminal bronchioles, budding air sacs, and alveoli, with
significant downregulation of expression as the rat matures. Parallel
immunostaining for surfactant proteins A and B, proliferating cell
nuclear antigen, and [3H]thymidine uptake studies
revealed that PTP-
was predominantly expressed in the
undifferentiated and proliferating fetal alveolar type II cells and
fetal Clara cells of the airways (9). Fetal type II cells
are the precursors for adult type II cells (10). Fetal
Clara cells are the stem cells of the small conducting airway epithelium and give rise to adult Clara cells and ciliated cells (10). Once differentiation was complete and proliferation
was reduced to the low level of epithelial cell turnover normally seen
in the quiescent healthy postnatal lung, PTP-
expression became
undetectable (9).
In the present study, the pulmonary PTP- expression pattern was
determined by Lac Z staining of the PTP-
/
and
PTP-
+/
mice. In agreement with our previous in situ
hybridization results in the rat lung (9), Lac Z staining
demonstrates expression of PTP-
in the airways and respiratory
epithelia of newborn mice; moreover, this expression is developmentally
downregulated. Although we previously failed to detect PTP-
expression in the rat pulmonary vasculature using in situ hybridization
(9), Lac Z staining (Fig. 1) clearly demonstrates
significant expression of PTP-
in the blood vessels (smooth muscle
and, possibly, endothelium). The reason for the lack of previous
detection of PTP-
in the vasculature is not known but may stem from
the different methodology employed, which may be less sensitive.
During the initial phenotypic analytic screen of the
PTP-/
mice, the occasional neonate was found to have
pulmonary edema (20). Subsequent systematic collection and
assessment of a large number of newborn PTP-
/
mice,
however, demonstrated that this was not a general phenomenon. H & E
analysis of PTP-
/
newborn lungs did not reveal
evidence of alveolar fluid (Fig. 3A). Wet-to-dry lung weight
ratios were similar in PTP-
/
,
PTP-
+/
, and PTP-
+/+ newborns, arguing
against the presence of alveolar fluid/pulmonary edema in the knockout
neonate (Fig. 2). On the basis of our recent and present work, we
conclude that the high neonatal mortality rate of the
PTP-
/
mice is the result of hypoglycemia, which at
least in part results from GH deficiency, and is not due to pulmonary
edema (1).
Airways of the PTP-/
mice appeared normal on H & E-stained sections and indistinguishable from the airways of
PTP-
+/
and PTP-
+/+ mice (Fig. 3). As
expected, PAS staining and diastase digestion revealed glycogen in
cells of the airways of PTP-
/
,
PTP-
+/
, and PTP-
+/+ newborn mice (Fig.
4). Many cell types of the neonatal lung, including Clara cells of the
airway and alveolar type II cells, have significant glycogen stores
(11). In the rat Clara cell, glycogen is immediately and
rapidly metabolized postpartum, so that within 48 h of birth there
is a massive decrease in the volume density (fraction of cell volume)
of glycogen. This is followed by a continual, but very gradual,
decrease of glycogen into adulthood. Glycogen mobilization at birth is
presumably important for the maturation of the secretory apparatus of
the Clara cell. In addition, because Clara cells are the progenitors
for the cells of the terminal bronchioles, glycogenolysis in Clara
cells may be critical for the proliferative burst they undergo during
the first 48 h after birth. Glycogen deposition and mobilization,
as assessed by PAS staining and diastase digestion, were similar
between PTP-
/
and PTP-
+/+ mice.
Ultrastructural analysis of different pulmonary epithelial cells,
including alveolar type II cells, Clara cells, and ciliated cells, did
not reveal any significant differences between the PTP-/
and PTP-
+/
or the
PTP-
+/+ mice (Figs. 5 and 6). The Clara cell population
demonstrated typical postnatal maturation changes (11)
when assessed in the three cohorts of animals. The type II cells and
ciliated cells of the airway in all three cohorts of the
PTP-
/
mice also appeared ultrastructurally normal.
We recently showed that the PTP-/
mouse demonstrates
significant abnormalities of the endocrine pancreas, pituitary, and
enteroendocrine cells of the gut (1). Here we assessed the
pulmonary neuroendocrine system by immunostaining for CGRP, a
predominant neuropeptide of mouse NEB. The NEB appeared normal in the
PTP-
/
mice and indistinguishable from the
immunostaining pattern in the PTP-
+/
and
PTP-
+/+ sibling control mice. In knockout mice lacking
mammalian achaete-scute homolog-1, a mammalian homolog of the
Drosophila achaete-scute genes, pulmonary NEB are completely
absent, but the pancreatic islets and enteroendocrine cells in the gut
develop and appear normal (2). These contrasting
phenotypes of the mammalian achaete-scute homolog-1 and PTP-
knockout mice suggest that the development and differentiation of the
neuroendocrine cell component of different endodermal derivatives
(i.e., gut, pancreas, and lung) are under tissue-specific regulatory control.
Although pulmonary mechanics were not formally assessed in this study,
no obvious abnormalities of ventilation were evident during routine
activity in the PTP-/
animals. Specifically, they
were not found to be tachypneic, nor was there any evidence of
increased respiratory effort.
In view of the tightly controlled and developmentally regulated
expression of PTP- within the lung, it was a surprise to see normal
lung architectural development in the PTP-
-deficient mouse. This is
particularly so when one considers that PTP-
is essential to the
development of other organs (e.g., central nervous system, peripheral
nervous system, pituitary), where a similar temporal expression
pattern is seen, and that mice deficient in receptors bearing a marked
resemblance to PTP-
demonstrate a dramatic lung phenotype. For
example, Dutt-1/Robo-1 is a mammalian transmembrane receptor possessing
an ectodomain very similar to PTP-
and the Ig family of neural CAMs
(24). The ectodomains of these proteins consist of repeats
of Ig-like domains and fibronectin type III repeats. Dutt-1 is probably
a tumor suppressor gene in mammals (24). It has also been
identified as the human homolog of the Drosophila roundabout
(Robo) (8) and has been proposed to play an essential role
in the guidance and migration of axons, myoblasts, and leukocytes in
vertebrates. In mice homozygous for a targeted mutation in the
Dutt-1/Robo-1 gene (which eliminates the first Ig domain of the
ectodomain), the lungs demonstrate mesenchyme expansion and extensive
bronchial epithelial hyperplasia (24). A 60% homozygote
neonatal mortality rate results from respiratory failure. We also noted
significant hyperplasia in the bronchial epithelium of one 2- to
3-wk-old PTP-
/
mouse. However, this finding was not
evident in the large majority of animals assessed.
In view of the normal lung architecture in the PTP--deficient mice,
one may speculate that, despite strong developmental expression of
PTP-
in the lung, either this protein does not play a significant
role in pulmonary development or, more likely, lung development in the
PTP-
knockout animals is "rescued" by the compensatory actions
of a closely related family member, such as LAR. Katsura and colleagues
(7) assessed the developmental expression profile of LAR
in the rat lung via immunohistochemistry and in situ hybridization.
They demonstrated that, in the lung, LAR is exclusively expressed in
the epithelium of the fetal airways and alveoli with persistent Clara
cell and alveolar type II cell expression throughout life. Thus LAR and
PTP-
are expressed in the same cell types within the rat lung. In
view of the similar expression patterns and extensive sequence homology
between the two proteins, it is not unreasonable to speculate that LAR
might rescue lung development in the PTP-
-deficient mouse. The LAR knockout mouse also lacks a lung phenotype (16-18,
26), and significant upregulation of PTP-
mRNA was observed
in the lungs of these knockout mice (W. Skarnes, personal
communication). Again, in this scenario, one might speculate that
rescue of the LAR-deficient mice by PTP-
would permit normal
pulmonary development.
PTP-, the third member of the mammalian LAR family, is also
expressed in the lung. Katsura et al. (7) demonstrated by in situ hybridization that PTP-
is expressed exclusively in the mesenchyme of the lung and that expression falls off significantly after birth. It is possible that PTP-
also plays a role in
rescue of the PTP-
knockout mouse, because
mesenchymal-epithelial interactions are critical during lung morphogenesis.
In conclusion, we have generated a PTP--deficient mouse and found
the lung architecture to be normal by detailed histological assessment.
We speculate that the presence and activity of the closely related
family members LAR and, possibly, PTP-
rescue and normalize lung
development in the absence of PTP-
in these mice. Although lung
architecture is not affected by the loss of PTP-
, pulmonary
mechanics, epithelial cell biology, and other lung functions of the
PTP-
/
mice have not been investigated and may be
affected by the loss of this phosphatase.
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ACKNOWLEDGEMENTS |
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We thank A. Giffin for assistance with mouse colony maintenance, J. Hwong for assistance with electron microscopy, and V. Wong for performing the CGRP immunostaining.
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FOOTNOTES |
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This work was supported by grants from the Canadian Institutes of Health Research (CIHR) to D. Rotin. J. Batt is supported by a CIHR fellowship. D. Rotin is the recipient of a CIHR Investigator Award.
Address for reprint requests and other correspondence: D. Rotin, Programs in Cell Biology, The Hospital for Sick Children, 555 University Ave., Toronto, ON, Canada M5G 1X8 (E-mail: drotin{at}sickkids.ca).
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.00069.2002
Received 25 February 2002; accepted in final form 19 August 2002.
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