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PubMed1984

Elastin metabolism and chemistry: potential roles in lung development and structure.

Elastic fibers are important for elasticity and extensibility of lung tissue. In the developing lung, elastic fibers appear in greatest numbers during the process or period of alveolarization . A variety of mesenchymal cells in lung appear responsible for elastin synthesis. Elastin is a novel protein both from the standpoint of its processing into elastic fibers and chemical properties. For example, elastin undergoes posttranslational modification before its assembly into fibers. These steps include limited proteolysis, hydroxylation of prolyl residues and the oxidative deamination of lysyl residues prior to their incorporation into the crosslinks that covalently bond together polypeptide chains of elastin. The crosslinking amino acids include lysinonorleucine , merodesmosine and desmosine isomers. A key enzyme that controls this process is lysyl oxidase. Lysyl oxidase is a copper metalloprotein whose activity is responsive to and modulated by environmental insults, nutrition deficiencies and the administration of various pharmacological agents. Regarding chemical properties, elastin is one of the most apolar proteins secreted by mammalian cells. Moreover, elastin is one of the most long-lived proteins secreted into the extracellular matrix. In relationship to its processing into elastic fibers and chemical properties, details related to major aspects of elastin metabolism as well as speculation on its potential as a factor in lung development and disease are discussed.

Amino Acids↗
PubMed1990

Differentiation-dependent expression of I and sialyl I antigens in the developing lung of human embryos and in lung cancers.

The localization of two carbohydrate antigens, I and sialyl I antigens, in the lungs of developing human embryos was investigated using specific monoclonal antibodies and compared with the distribution patterns of the known embryonic antigen, stage-specific embryonic antigen-1 (Lex hapten). When the future bronchi were actively developing from the bronchial buds in the lungs of 50- to 53-day-old embryos, the immature bronchial bud cells were I-, Lex+, while the fully differentiated epithelial cells of the larger bronchus were I+, Lex-. When the bronchiolar bud cells matured into bronchiolar epithelial cells in the lung of a 12-week-old embryo, the immature bronchiolar bud cells were I-,Lex+, while the fully differentiated epithelial cells of the bronchioles were I+,Lex-. Sialylated forms of the antigens finally appeared in the lungs of 18-week-old embryos, when the terminal bud cells actively proliferated and underwent the differentiation process into epithelial cells of alveoli and alveolar ducts. The immature terminal bud cells at this stage were I-, sialyl I-, Lex+, sialyl Lex-i+, while the fully differentiated alveolar epithelial cells were I+, sialyl I+, Lex-, sialyl Lex-i-. After 8 months, the flattened mature alveolar epithelial cells were strongly positive for both I and sialyl I antigens, the strong expression of which continued after birth and even into the adult stage. These distribution patterns indicate that the I and sialyl I antigens are specific markers for the differentiated type cells in each stage of development, while Lex and related embryonic antigens were specific to the immature bud cells in every stage. The above-described differentiation-dependent expression patterns of these antigens seem to be reflected in the distribution of these antigens in human lung cancers, i.e., I and sialyl I antigens were expressed in lung cancer cells more weakly than in normal lung cells, while the Lex and sialyl Lex-i were expressed in cancer cells much more strongly than in normal lung cells. This was further reflected in the serum levels of these antigens in the patients with respiratory disorders. The distribution pattern of the serum levels of these antigens in patients with lung cancers showed sialyl Lex-i greater than sialyl I, indicating that these serum antigens originated from the lung cancer lesion where sialyl Lex-i is much more dominant than sialyl I antigen.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1999

Prenatal nicotine increases pulmonary alpha7 nicotinic receptor expression and alters fetal lung development in monkeys.

It is well established that maternal smoking during pregnancy is a leading preventable cause of low birth weight and prematurity. Less appreciated is that maternal smoking during pregnancy is also associated with alterations in pulmonary function at birth and greater incidence of respiratory illnesses after birth. To determine if this is the direct result of nicotine interacting with nicotinic cholinergic receptors (nAChRs) during lung development, rhesus monkeys were treated with 1 mg/kg/day of nicotine from days 26 to 134 of pregnancy. Nicotine administration caused lung hypoplasia and reduced surface complexity of developing alveoli. Immunohistochemistry and in situ alpha-bungarotoxin (alphaBGT) binding showed that alpha7 nAChRs are present in the developing lung in airway epithelial cells, cells surrounding large airways and blood vessels, alveolar type II cells, free alveolar macrophages, and pulmonary neuroendocrine cells (PNEC). As detected both by immunohistochemistry and by alphaBGT binding, nicotine administration markedly increased alpha7 receptor subunit expression and binding in the fetal lung. Correlating with areas of increased alpha7 expression, collagen expression surrounding large airways and vessels was significantly increased. Nicotine also significantly increased numbers of type II cells and neuroendocrine cells in neuroepithelial bodies. These findings demonstrate that nicotine can alter fetal monkey lung development by crossing the placenta to interact directly with nicotinic receptors on non-neuronal cells in the developing lung, and that similar effects likely occur in human infants whose mothers smoke during pregnancy.

Animals↗
PubMed2006

Wnt signalling in lung development and diseases.

There are several signalling pathways involved in lung organogenesis including Notch, TGFbeta/BMP, Sonic hedgehog (Shh), FGF, EGF, and Wnt. Despite the widely acknowledged significance of Wnt signalling in embryonic lung development, the role of different Wnt pathways in lung pathologies has been slow to emerge. In this review, we will present a synopsis of current Wnt research with particular attention paid to the role of Wnt signals in lung development and in pulmonary diseases.

Animals↗
PubMed2002

Keratinocyte and hepatocyte growth factors in the lung: roles in lung development, inflammation, and repair.

A growing body of evidence indicates that the epithelial-specific growth factors keratinocyte growth factor (KGF), fibroblast growth factor (FGF)-10, and hepatocyte growth factor (HGF) play important roles in lung development, lung inflammation, and repair. The therapeutic potential of these growth factors in lung disease has yet to be fully explored. KGF has been best studied and has impressive protective effects against a wide variety of injurious stimuli when given as a pretreatment in animal models. Whether this protective effect could translate to a treatment effect in humans with acute lung injury needs to be investigated. FGF-10 and HGF may also have therapeutic potential, but more extensive studies in animal models are needed. Because HGF lacks true epithelial specificity, it may have less potential than KGF and FGF-10 as a targeted therapy to facilitate lung epithelial repair. Regardless of their therapeutic potential, studies of the unique roles played by these growth factors in the pathogenesis and the resolution of acute lung injury and other lung diseases will continue to enhance our understanding of the complex pathophysiology of inflammation and repair in the lung.

Animals↗
PubMed1995

Tenascin in rat lung development: in situ localization and cellular sources.

Tenascin (TN) is a hexameric extracellular matrix glycoprotein that may play an important role during lung development. TN protein is temporally and spatially restricted during lung organogenesis. The temporo-spatial and cellular expression of TN mRNA in lung remains unclear. Localization of message expression of TN in rat lung tissue was first investigated by using in situ hybridization performed with an antisense RNA probe. TN mRNA was present primarily within the mesenchyme of day 16 gestational age fetal rat lung tissue, whereas immunoreactive TN protein was found along the basement membrane. In postnatal day 3 rat lung tissue, TN mRNA was detected along alveolar septal walls and was concentrated at secondary septal tips. Expression of TN message was consistent with localization of immunoreactive TN protein. Accumulation of TN mRNA in alveolar septal tips suggests that mesenchyme may be the major source of TN mRNA. To investigate the cellular source of TN in rat lung, we studied the expression of TN in cultured rat lung fibroblasts, endothelial cells, and alveolar epithelial cells. Two TN isoforms having molecular mass of 230 and 180 kDa were in conditioned medium and in cellular extracts of lung fibroblasts and endothelial cells. TN was secreted and deposited in the extracellular matrix closely associated with the surface of lung fibroblasts and endothelial cells. Lung alveolar epithelial cells showed undetectable or barely detectable amounts of TN. These studies demonstrated that TN isoforms are expressed not only by lung fibroblasts but also by lung endothelial cells. The unique spatial localization of TN mRNA during lung development and expression of TN by different lung cell types suggested TN may be involved in matrix organization and cell-cell interactions during lung development.

Aging↗
PubMed1993

Regulation of proto-oncogene expression in adult and developing lungs.

Activation of immediate-early gene expression has been associated with mitogenesis, differentiation, nerve cell depolarization, and recently, terminal differentiation processes and programmed cell death. Previous evidence also suggested that immediate-early genes play a role in the physiology of the lungs (J. I. Morgan, D. R. Cohen, J. L. Hempstead, and T. Curran, Science 237:192-197, 1987). Therefore, we analyzed c-fos expression in adult and developing lung tissues. Seizures elicited by chemoconvulsants induced expression of mRNA for c-fos, c-jun, and junB and Fos-like immunoreactivity in lung tissue. The use of pharmacological antagonists and adrenalectomy indicated that this increased expression was neurogenic. Interestingly, by using a fos-lacZ transgenic mouse, it was shown that Fos-LacZ expression in response to seizure occurred preferentially in clusters of epithelial cells at the poles of the bronchioles. This was the same location of Fos-LacZ expression detected during early lung development. These data imply that pharmacological induction of immediate-early gene expression in adult mice recapitulates an embryological program of gene expression.

Adrenalectomy↗
PubMed2002

The alpha-isoform of caveolin-1 is a marker of vasculogenesis in early lung development.

Caveolin-1 is a scaffolding protein component of caveolae, membrane invaginations involved in endocytosis, signal transduction, trans- and intracellular trafficking, and protein sorting. In adult lung, caveolae and caveolin-1 are present in alveolar endothelium and Type I epithelial cells but rarely in Type II cells. We have analyzed patterns of caveolin-1 expression during mouse lung development. Two caveolin-1 mRNAs, full-length and a 5' variant that will translate mainly into caveolin-1alpha and -beta isoforms, are detected by RT-PCR at embryonic day 12 (E12) and afterwards in the developing and adult lung. Immunostaining analysis, starting at E10, shows caveolin-1alpha localized in primitive blood vessels of the forming lung, in an overlapping pattern to the endothelial marker PECAM-1, and later in all blood vessels. Caveolin-1alpha is not detected in fetal or neonatal lung epithelium but is detected in adult epithelial Type I cells. Caveolin-1 was previously shown to be expressed in alveolar Type I cells. These data suggest that expression of caveolin-1 isoforms is differentially regulated in endothelial and epithelial cells during lung development. Caveolin-1alpha is an early marker for lung vasculogenesis, primarily expressed in developing blood vessels. When the lung is fully differentiated postnatally, caveolin-1alpha is also expressed in alveolar Type I cells.

Animals↗
PubMed2002

Neuronal developmental marker FORSE-1 identifies a putative progenitor of the pulmonary neuroendocrine cell lineage during lung development.

The FORSE-1 (forebrain-surface-embryonic) monoclonal antibody (MAb) recognizes a carbohydrate cell surface epitope related to the Lewis-X (LeX) and stage-specific embryonic antigens (SSEAs). In the developing CNS, the FORSE-1 epitope is believed to serve as a marker of progenitor cells. We studied the expression of the FORSE-1 epitope in pulmonary neuroendocrine cells (PNECs) and related neuroepithelial bodies (NEBs), cell types implicated in paracrine regulation of lung development. We used dual immunolabeling to identify PNECs/NEBs in tissue sections from developing rabbit fetal lungs and corresponding primary lung cell cultures. During the early stage (E16), the FORSE-1 MAb labeled primitive airway epithelium, whereas serotonin (5HT) immunoreactivity, a marker of PNEC/NEB differentiation, was negative. After E18, FORSE-1 labeling became restricted to PNECs and NEBs, identified by co-expression with 5HT, then decreased coincident with an increase in 5HT. Expression of the FORSE-1 epitope correlated inversely with 5HT expression in PNEC/NEB cells. FORSE-1 immunoreactivity correlated with cell proliferation assessed by BrdU labeling. Downregulation of the FORSE-1 epitope correlated with maturation of PNECs/NEBs. The presence of few FORSE-1/5HT-positive cells in postnatal lung suggests retention of progenitors. The FORSE-1 epitope was associated with a high molecular weight (286 kD) glycoprotein that decreased with increasing gestational age, as demonstrated by immunoblotting. Overall expression of SSEA-1, -3, and -4 antigens was similar to FORSE-1/5HT, although the former was preferentially localized to neurite-like processes. Because the role of the FORSE-1 epitope in the CNS probably involves cell adhesion and differentiation, we propose a similar function in developing lung. The demonstration of LeX/SSEA antigen expression in the PNEC/NEB cell lineage underscores the importance of these cells in developing lung. Furthermore, the FORSE-1 antigen may identify committed progenitors of the PNEC/NEB cell system.

Animals↗
PubMed2006

Over-expression of PDGF-C using a lung specific promoter results in abnormal lung development.

PDGF isoforms are a family of polypeptides that bind to cell surface receptors and induce fibroblast proliferation and chemotaxis. PDGF-A and -B chain isoforms have previously been shown to be involved in murine lung development. A new PDGF polypeptide, PDGF-C, was recently recognized and differs from the PDGF-A and -B isoforms in that it requires proteolytic cleavage before it can bind and activate the PDGF alpha receptor. In these studies PDGF-C was over-expressed during embryogenesis using the lung specific surfactant protein C promoter. PDGF-C transgenic pups died from respiratory insufficiency within minutes following birth. At E18.5, nontransgenic lungs exhibited lung morphology consistent with the saccular stage of lung development. In contrast, E18.5 transgenic lungs retained many features of the canalicular stage of lung development and had abundant numbers of large poorly differentiated mesenchymal cells. These results suggest that PDGF-C is activated during lung development and is a potent growth factor for mesenchymal cells in vivo.

Animals↗
PubMed2005

Wnt5a regulates Shh and Fgf10 signaling during lung development.

The role of WNT signaling and its interactions with other morphogenetic pathways were investigated during lung development. Previously, we showed that targeted disruption of Wnt5a results in over-branching of the epithelium and thickening of the interstitium in embryonic lungs. In this study, we generated and characterized transgenic mice with lung-specific over-expression of Wnt5a from the SpC promoter. Over-expression of Wnt5a interfered with normal epithelial-mesenchymal interactions resulting in reduced epithelial branching and dilated distal airways. During early lung development, over-expression of Wnt5a in the epithelium resulted in increased Fgf10 in the mesenchyme and decreased Shh in the epithelium. Both levels and distribution of SHH receptor, Ptc were reduced in SpC-Wnt5a transgenic lungs and were reciprocally correlated to changes of Fgf10 in the mesenchyme, suggesting that SHH signaling is decreased by over-expression of Wnt5a. Cultured mesenchyme-free epithelial explants from SpC-Wnt5a transgenic lungs responded abnormally to recombinant FGF10 supplied uniformly in the Matrigel with dilated branch tips that mimic the in vivo phenotype. In contrast, chemotaxis of transgenic epithelial explants towards a directional FGF10 source was inhibited. These suggest that over-expression of Wnt5a disrupts epithelial-response to FGF10. In conclusion, Wnt5a regulates SHH and FGF10 signaling during lung development.

Animals↗
PubMed1998

Ontogeny of apoptosis during lung development.

Apoptosis has been shown to be involved in several processes during embryogenesis, but the ontogeny of apoptosis during lung development ahs not been studied. The goals of the current study were to determine if apoptosis occurs during lung development, and to determine the ontogeny of the changes in apoptosis that occur. We studied the ontogeny of apoptosis in vivo using lungs from 14-18-d gestation fetal rats, newborn rats, and 1-d-, 2-d-, 5-d-, and 10-d-old rat pups. Apoptosis was assessed by electron microscopy and the terminal deoxyribonucleotidyl transferase dUTP nick end-labeling assay. We compared the in vivo results with explants of 14-d gestation fetal rat lung placed in culture for 1-4 d because the biochemical development of the lung in organ culture has been shown to closely parallel the development of the lung in vivo. We found apoptosis of mesenchymal cells at the periphery of distal lung buds in early fetal lung (14-16-d gestation). Apoptosis of both mesenchyme and epithelium was present in later fetal lung (18-d gestation). There were no qualitative differences in apoptosis between in vivo fetal lung and explant cultures of fetal lung. There was a 14-fold increase in apoptosis at birth and in the first postnatal day of life (9-12% of cells) compared with fetal lung (0.6-1% of cells). This was followed by a rapid decline in the percentage of apoptotic cells to fetal levels at postnatal d 2-10. We conclude that apoptosis occurs in a spatially, temporally, and cell-specific manner during lung development. The number of cells undergoing apoptosis increases dramatically in the first day after birth.

Animals↗
PubMed1998

Paracrine mediators of mechanotransduction in lung development.

The process of normal fetal lung development is dependent on "mild" tissue distension (approximately 3 mm Hg) by fluid, resulting in the production of pulmonary surfactant which is necessary for survival at the time of birth. The mechanical "stretching" of lung tissue triggers a cellular differentiation cycle, in part by stimulating the expression and production of cell phenotype-specific soluble cytokines. Pulmonary cytokines regulate differentiation and metabolic function of neighboring cells. For example, tonic stretching of type II alveolar epithelial cells in monolayer culture stimulates the expression and production of the differentiation factor parathyroid hormone-related peptide (PTHrP), which is released by type II cells and specifically binds to its receptor on contiguous fibroblasts, stimulating the "second messenger" cyclic AMP. Tonic distension of cultured type II cells increases PTHrP production, and distension of fibroblasts in monolayer culture increases their PTHrP responsiveness, suggesting that stretching couples and coordinates the production and receptor-mediated action of PTHrP. These data provide a mechanistic basis for the previously observed hand-in-glove spatial pattern of PTHrP and the PTHrP receptor (PTHrPR) in developing terminal airways. PTHrP stimulates specific differentiated functions of fetal lung fibroblasts by: 1) augmenting glucocorticoid binding; 2) increasing metabolic activities directly related to surfactant synthesis, such as lipoprotein lipase elaboration and triglyceride uptake rate; 3) stimulating cytokines, such as interleukins 6 and 11, that can act in a retrograde fashion on epithelial cells; 4) thereby increasing the synthesis of surfactant phospholipids and surfactant-associated proteins, closing this stretch-mediated cell-cell interactive loop. Experimental interruption of this mechanism at any of these steps blocks the spontaneous maturation of the lung in vitro, as evidenced by the inhibition of surfactant production.

Animals↗
PubMed1994

Late appearance of a type I alveolar epithelial cell marker during fetal rat lung development.

Recent studies in fetal lung using immunological and molecular probes have revealed type I and type II cell phenotypic markers in primordial lung epithelial cells prior to the morphogenesis of these cell types. We have recently developed monoclonal antibodies specific for adult type I cells. To evaluate further the temporal appearance of the type I cell phenotype during alveolar epithelial cell ontogeny, we analyzed fetal lung development using one of our monoclonal antibodies (mAb VIII B2). The epitope recognized by mAb VIII B2 first appears in the canalicular stage of fetal lung development, at approx. embryonic day 19 (E19), in occasional, faintly stained tubules. Staining with this type I cell probe becomes more intense and more widespread with increasing gestational age, during which time the pattern of staining changes. Initially, all cells of the distal epithelial tubules are uniformly labelled along their apical and basolateral surfaces. As morphological differentiation of the alveolar epithelium proceeds, type I cell immunoreactivity appears to become restricted to the apical surface of the primitive type I cells in a pattern approaching that seen in the mature lung. We concurrently analyzed developing fetal lung with an antiserum to surfactant apoprotein-A (alpha-SP-A). Consistent with the findings of others, labeling of SP-A was first detectable in scattered cuboidal cells at E18. Careful examination of the double-labeled specimens suggested that some cells were reactive with both the VIII B2 and SP-A antibodies, particularly at E20. Confocal microscopic analysis of such sections from E20 lung confirmed this impression. Three populations of cells were detected: cells labeled only with alpha-SP-A, cells labeled only with mAb VIII B2, and a smaller subset of cells labeled by both.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

The effect of maternal exercise on somatic growth and lung development of fetal rats: morphologic and morphometric studies.

Our study was aimed at elucidating the effect of strenuous maternal exercise (running at a speed of 20 m/min) on fetal somatic growth and lung development. Dams were separated into three groups: (1) exercising during the entire course of pregnancy; (2) exercising from the 16th to the 20th gestational day; and (3) controls treated in the same manner as the exercising animals, but not exercised. There were no differences in the mother's body weight (mother's body weight--total body weight of the fetuses) among the three groups. Overall growth and lung development in fetuses from mothers that exercised during the entire course of pregnancy showed markedly decreased size and weight of body and lung, smaller air spaces and thicker future alveolar walls, and fewer osmiophilic lamellated bodies in alveolar type II cells. The morphometric data of fetuses from mothers that had exercised only during late gestation were similar to those of control animals. The ratio of fetal lung volume to body weight was the same in all three groups. These findings indicate that long-term strenuous maternal exercise induces retardation of fetal lung development, possibly accompanied by a disturbance of overall growth. Maternal exercise represents another means of manipulating lung development.

Animals↗
PubMed1987

Induction and characterization of the major surfactant apoprotein during rabbit fetal lung development.

Antibodies directed against the major apoprotein associated with rabbit lung surfactant were used to characterize the induction and cellular localization of this protein during rabbit fetal lung development. In lung tissues from rabbits of 26 days gestational age and older, discrete epithelial type II cells were stained positively using the peroxidase antiperoxidase technique. The content of the major protein in homogenates of fetal lung tissue was analyzed using an immunoblotting technique. A protein of about 29 kDa, pI less than or equal to 5.6, was first detectable in fetal lung tissue on day 24 of gestation. The 29-36 kDa, mature form of the surfactant apoprotein was first detectable in lung homogenates from 30-day gestational age fetal rabbits. Treatment of homogenates of day 26 and 31 fetal lung tissues with endoglycosidase F, yielded, in both cases, an immunoreactive triplet with more neutral isoelectric points than the proteins in the untreated homogenates. By immunoblot analysis, we found that only the 29-36 kDa, mature form of the surfactant apoprotein was present in lamellar bodies purified from lung tissues of fetuses of 28 and 31 days and from day 2 neonates. These findings are suggestive that only the mature, 29-36 kDa form of the surfactant apoprotein is associated with lamellar bodies during fetal lung type II cell differentiation in vivo.

Animals↗
PubMed1995

Characterization of alpha 1, beta 1, and gamma 1 laminin subunits during rabbit fetal lung development.

Laminin-1 is an extracellular matrix protein composed of three polypeptide chains that are designated alpha 1, beta 1, and gamma 1. We investigated the expression of laminin alpha 1, beta 1, and gamma 1 subunit chains during several stages of rabbit fetal lung development. Utilizing polyclonal antibodies directed against human placental laminin and immunoblot analysis, we found that the highest levels of laminin alpha 1, beta 1, and gamma 1 subunit chains in the fetal lung were present on day 26 of gestation (term = 31 days), coincident with the initiation of alveolar epithelial cell differentiation. Levels of the laminin chains were approximately five times higher in fetal lung at day 26 of gestation than in adult lung tissue. Different temporal patterns of laminin alpha 1, beta 1, and gamma 1 subunit chain expression were observed, data suggestive that the chains are independently regulated during lung development. Laminin was localized to the basement membranes of bronchi, bronchioles, prealveolar ducts, and blood vessels in fetal lung tissue, as shown by immunostaining with polyclonal laminin antibodies. A similar staining pattern was observed in adult lung tissue, but the alveolar wall was also stained. Laminin was also observed surrounding a few mesenchymal cells in fetal lung on day 19 of gestation; the number of positive mesenchymal cells increased with lung development. Laminin alpha 1 subunit chains, detected using a monoclonal antibody, were present in the basement membranes of bronchi, bronchioles, prealveolar ducts, and blood vessels in fetal lung tissue. No laminin alpha 1 chain staining was observed in the mesenchyme of early fetal lung tissue. Using a monoclonal antibody, laminin beta 1 subunit chains were immunolocalized in the basement membranes of bronchi, bronchioles, in prealveolar ducts, and surrounding some mesenchymal cells in fetal lung tissue. Laminin alpha 1 and beta 1 subunit chains in adult lung tissue were present in basement membranes of airways, blood vessels, and alveoli. Thus, changes in the localization and accumulation of laminin near the time of alveolar type I and type II epithelial cell differentiation suggest that laminin may play a role in mediating the differentiation of these cell types during rabbit fetal lung development.

Animals↗
PubMed1997

Evidence for the involvement of the Gli gene family in embryonic mouse lung development.

Murine Gli, Gli2, and Gli3 are zinc finger genes related to Drosophila cubitus interuptus, a component of the hedgehog signal transduction pathway. In the embryonic lung, all three Gli genes are strongly expressed at the pseudoglandular stage, in distinct but overlapping domains of the mesoderm. Expression of Gli and Gli3, but not of Gli2, is subsequently downregulated at the canalicular stage, coincident with a decline in the expression of sonic hedgehog (Shh) and the hedgehog receptor gene, patched (Ptc). Overexpression of Shh in the lung results in increased levels of Ptc mRNA. Gli, but not Gli2, is also upregulated, suggesting a differential involvement of the Gli genes in the regulation of Ptc by SHH during lung development. Gli3 is not upregulated by Shh overexpression. However, its importance for lung development is shown by the finding that Gli3XtJ embryos, homozygous for a mutation involving a deletion of the Gli3 gene, have a stereotypic pattern of abnormalities in lung morphogenesis. The pulmonary defects in these embryos, consisting of localized shape changes and size reductions, correlate with normal Gli3 expression. Thus, our data indicate that one of the Gli genes, Gli3, is essential for normal lung development, and that another, Gli, can be placed downstream of Shh signaling in the lung.

Animals↗