Late gestational lung hypoplasia in a mouse model of the Smith-Lemli-Opitz syndrome (original) (raw)
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Developmental Dynamics, 2001
Holoprosencephaly is a common developmental anomaly of the forebrain and midface, that has been associated with mutations in the Sonic Hedgehog gene, and with perturbations of cholesterol synthesis and metabolism in mammalian embryos. The study presented here was aimed to evaluate the functional relationship between these two causal agents in the genesis of the phenotype. Therefore, we used rat embryos exposed in utero to a distal inhibitor of cholesterol biosynthesis (AY9944) in which we analyzed different Shh-dependent processes, as evaluated by the expression of eight target genes. In addition, to delineate between the impact of cholesterol shortage and/or sterol precursors accumulation on the Shh signaling cascade we exposed rat embryos to AY9944 and we provided complementary diets rich in cholesterol and 7-DHC. At the early-somite stage we observed a reduction of Shh signaling in AY9944 treated embryos, resulting in the definition of a narrower ventral domain. Later in development this reduction of Shh signaling led to a complete interruption of the pathway in the rostral hindbrain and caudal midbrain. Other regions such as the forebrain and the spinal cord appeared less sensitive to the reduction of Shh signaling and interruption of the pathway was only observed in a subset of embryos. Finally, we did provide evidence that 7-DHC accumulation is compatible with normal activity of Shh, as long as cholesterol levels in embryonic tissue is sufficient.
Molecular and Physiological Determinants of Pulmonary Developmental Biology: a Review
American Journal of Biomedical Research, 2013
The lungs undergo an extensive endodermal diverging morphogenesis along with alveogenesis, angiogenesis, and vasculogenesis to secure a sufficient diffusion surface for gaseous exchange. Any aberration in the course of normal development inculcating structural and functional abnormalities of lungs in antenatal life has potential morbidity in adult life. Factors such as IUGR, nutrient deficiency, FLM, Hypoxemia, ETS, surfactant deficiency, allergy and infections can adversely affect in-utero lungs development. Peculiar local and systemic inflammatory immune responses may elicit persistent architectural and physiological abnormalities. Lung surfactant produced by AEC-II cells is a mixture of phospholipids, surfactant proteins, and neutral lipids. Surfactant lowers alveolar surface tension, a crucial step for the prevention of alveolar collapse. Surfactant proteins are part of the innate immune defense of the lung. Surfactant deficiency and dysfunction is known to implicate a number of respiratory diseases especially allergic asthma and NRDS. The present article provides a state of the art review of the current knowledge of biology of normal lung development, its anatomical and molecular aspects, factors that regulate normal organogenesis of pulmonary system and molecular basis of respiratory allergic disorders including asthma.
Journal of Biological Chemistry, 2008
Neonatal respiratory distress syndrome (RDS) is mainly the result of perturbation in surfactant production and is a common complication seen in premature infants. Normal fetal lung development and alveolar cell differentiation is regulated by a network of transcription factors. Functional loss of any of these factors will alter the developmental program and impact surfactant production and normal gas exchange. During development, the fetus is exposed to varying oxygen concentrations and must be able to quickly adapt to these changes in order to survive. Hypoxia-inducible factor 1␣ (HIF1␣) is the primary transcription factor that is responsible for regulating the cellular response to changes in oxygen tension and is essential for normal development. Its role in lung maturation is not well defined and to address this knowledge gap, a lung-specific HIF1␣ knockout model has been developed. Loss of HIF1␣ early in lung development leads to pups that die within hours of parturition, exhibiting symptoms similar to RDS. Lungs from these pups display impaired alveolar epithelial differentiation and an almost complete loss of surfactant protein expression. Ultrastructural analysis of lungs from HIF1␣ deletion pups had high levels of glycogen, aberrant septal development, and decreased expression of several factors necessary for proper lung development, including HIF2␣, -catenin, and vascular endothelial growth factor. These results suggest that HIF1␣ is essential for proper lung maturation and alteration in its normal signaling during premature delivery might explain the pathophysiology of neonatal RDS. During development, an embryo is exposed to varying levels of oxygen as a balance is created between vascularization and tissue growth. Localized hypoxia, a decrease in available oxygen, is a normal part of this process. The programmed responses to these decreases in available oxygen are essential for viability (1, 2). In utero, the embryo is supplied with oxygen and nutrients through the placental barrier. Following parturition, oxygen is supplied by the neonatal lungs and therefore, proper intrauterine development of the alveolar gas exchange regions of the lung is essential for the newborn's first breath and for sustaining life outside the womb (3). Lung morphogenesis is a complex process that is orchestrated by several transcription factors, growth factors, and extracellular cues (4). For example, thyroid transcription factor-1 regulates the expression of the genes for Clara cell secretory protein (CCSP) 2 produced in Clara cells in the tracheobronchial airways and various surfactants produced by alveolar type II cells in the lung parenchyma (5, 6). CCAAT-enhancerbinding protein ␣ (CEBP␣) is essential for proper regulation of alveolar Type II cell differentiation, and Forkhead box A2 (Foxa2) controls various cellular programs involved in lung development (e.g. surfactant expression) (6-8). Ablation of any of these factors results in major structural and functional abnormalities ranging from undeveloped alveolar structure and/or improper airway branching to the faulty processing of various secretory components (7, 8). One of the extracellular cues that is important for fetal vascular growth and lung morphogenesis is the physiologically low O 2 environment of the fetus. The ability to cope with this developmental "hypoxia" is not only important for lung maturation but essential for the viability of the fetus (1, 2). Cellular responses to decreased oxygen availability are regulated by a family of proteins called hypoxia-inducible factors (HIFs). The ability of HIFs to respond to hypoxia is controlled by oxygen-dependent post-translational hydroxylation. The prolyl hydroxylases, PHDs, modify HIFs on essential residues in an oxygen-, iron-, and ␣-ketoglutarate-dependent manner. Once hydroxylated, the HIF is quickly degraded in a proteosomal-dependent process that involves the Von Hippel Lindau (VHL) tumor suppressor. HIF1␣, the most ubiquitously expressed HIF, has been shown to play a critical role in normal
Effect of maternal food restriction on fetal rat lung lipid differentiation program
Pediatric Pulmonology, 2009
Although "fetal programming" has been extensively studied in many organs, there is only limited information on pulmonary effects in the offspring following intrauterine growth restriction (IUGR). We aimed to determine the effects of nutrient restriction on the lung structure and lung lipid differentiation programs in offspring using an animal mode of maternal food restriction (MFR). We utilized a rodent model of 50% MFR from day 10 of gestation to term and then using lung morphology, Western blotting, Real Time-RT-PCR and oil red O staining, lung structure and development of the offspring were examined at postnatal days (p) 1, p21, and 9 months (9M). At postnatal day 1, MFR pups weighed significantly less compared to control pups, but at p21 and 9M, they weighed significantly more. However, lung weight, expressed as a percentage of body weight between the two groups was not different at all time-points examined. The MFR group had significantly decreased alveolar number and significantly increased septal thickness at p1 and 9M, indicating significantly altered lung structure in the MFR offspring. Furthermore, although at p1, compared to the control group, lung lipid accumulation was significantly decreased in the MFR group, at 9M, it was significantly increased. There were significant temporal changes in the Parathyroid Hormone-related Protein/Peroxisome Proliferator-Activated Receptor gamma signaling pathway and surfactant synthesis. We conclude that MFR alters fetal lung lipid differentiation programming and lung morphometry by affecting specific epithelial-mesenchymal signaling pathways, offering the possibility for specific interventions to overcome these effects.
Androgen Regulation of Signaling Pathways in Late Fetal Mouse Lung Development 1
Endocrinology, 2000
During lung development there is tension between positive and negative regulators of fibroblast-epithelial communication controlling type II cell differentiation. A clinical consequence of imbalance of this tension is the increased risk for respiratory distress syndrome in male infants. We hypothesized that chronic intrauterine androgen exposure alters fetal lung fibroblast maturation by down-regulating epidermal growth factor receptor (EGF-R) activity and by up-regulating transforming growth factor- receptor (TGF-R) activity, leading to an inhibition of surfactant protein B (SP-B) and -C (SP-C) gene expression in type II cells. We treated pregnant mice with dihydrotestosterone (DHT; 2 mg/day) or vehicle for 7 days, starting on gestational day 11. On day 18, EGF binding, EGF-R phosphorylation, TGF-R binding, and TGF1-induced cell proliferation were studied in sex-specific fibroblast cultures. SP-B and -C messenger RNA levels were measured in whole lungs. Chronic DHT treatment reduced both EGF binding (females to 78 Ϯ 8% and males to 65 Ϯ 9% of controls) and EGF-induced EGF-R phosphorylation. TGF-R binding was increased (females to 173 Ϯ 39% and males to 280 Ϯ 64% of controls), and TGF-induced cell proliferation was increased in female cells (231 Ϯ 57% of controls). SP-B and -C messenger RNA expression was reduced to 55 Ϯ 10% and 75 Ϯ 4%, respectively. We conclude that chronic DHT exposure beginning early in lung development alters the balance of growth factor signaling that regulates lung maturation.
Androgen Regulation of Signaling Pathways in Late Fetal Mouse Lung Development
Endocrinology, 2000
During lung development there is tension between positive and negative regulators of fibroblast-epithelial communication controlling type II cell differentiation. A clinical consequence of imbalance of this tension is the increased risk for respiratory distress syndrome in male infants. We hypothesized that chronic intrauterine androgen exposure alters fetal lung fibroblast maturation by down-regulating epidermal growth factor receptor (EGF-R) activity and by up-regulating transforming growth factor- receptor (TGF-R) activity, leading to an inhibition of surfactant protein B (SP-B) and -C (SP-C) gene expression in type II cells. We treated pregnant mice with dihydrotestosterone (DHT; 2 mg/day) or vehicle for 7 days, starting on gestational day 11. On day 18, EGF binding, EGF-R phosphorylation, TGF-R binding, and TGF1-induced cell proliferation were studied in sex-specific fibroblast cultures. SP-B and -C messenger RNA levels were measured in whole lungs. Chronic DHT treatment reduced both EGF binding (females to 78 Ϯ 8% and males to 65 Ϯ 9% of controls) and EGF-induced EGF-R phosphorylation. TGF-R binding was increased (females to 173 Ϯ 39% and males to 280 Ϯ 64% of controls), and TGF-induced cell proliferation was increased in female cells (231 Ϯ 57% of controls). SP-B and -C messenger RNA expression was reduced to 55 Ϯ 10% and 75 Ϯ 4%, respectively. We conclude that chronic DHT exposure beginning early in lung development alters the balance of growth factor signaling that regulates lung maturation.
FEBS Letters, 2000
In order to address the biological function of GlcNAc N-deacetylase/N-sulfotransferase-1 (NDST-1), we disrupted the NDST-1 gene by homologous recombination in mouse embryonic stem cells. The NDST-1 null mice developed respiratory distress and atelectasis that subsequently caused neonatal death. Morphological examination revealed type II pneumocyte immaturity, which was characterized by an increased glycogen content and a reduced number of lamellar bodies and microvilli. Biochemical analysis further indicated that both total phospholipids and disaturated phosphatidylcholine were reduced in the mutant lung. Our data revealed that NDST-1 was essential for the maturation of type II pneumocytes and its inactivation led to a neonatal respiratory distress syndrome.
BMC Research Notes, 2011
Background: Expression of apolipoprotein A-I (apoA-I), A-II, and H was previously observed at 16 to 50-fold higher levels in the fetal than the adult mouse lung. Here, sites of apoA-I, A-II, and H mRNA and protein accumulation were determined in mouse fetal lungs by in situ hybridization and immunohistochemistry in late gestation. Results: Expression sites vary for the three genes and change for the distal epithelium before the end of the canalicular stage, thus where and when the surge of surfactant synthesis occurs. Messenger of apoH, but not those of apoA-I and A-II, was also observed in the proximal epithelium and smooth muscles surrounding arteries. In contrast to apoC-II protein, none of the three studied apolipoproteins accumulated within secretory granule-like structures. Immunohistochemistry revealed that apoA-I and apoH accumulated mainly in capillaries. Three different positive signals with the anti-apoA-II antibody were found: one transient signal in the nucleus of a portion of mesenchymal cells, a second at lower levels throughout the mesenchyme, and another in capillaries with a specific increase from gestation day 17.5/18.5. Conclusion: Temporal and geographic co-expression of apoAI, AII, and H genes with surfactant production site suggests that the three apolipoproteins are secreted to play roles supporting the lung-specific surfactant lipidrelated metabolism.