Thyroid transcription factor-1 expression during normal human lung development and in patients with congenital diaphragmatic hernia

Hoşgör, Münevver; IJzendoorn, Ynske; Mooi, Wolter J.; Tibboel, Dick; Krijger, Ronald R. de

doi:10.1053/jpsu.2002.34977

Cited by 16 publications

(10 citation statements)

References 18 publications

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“…No developmental change was observed for proSP-C because it does not accumulate in the developing lung, unlike mature proteins [43]. Considering the role of TTF1 as a transcription regulator of SPs [39], the absence of any change in SP content is fully consistent with unchanged TTF1 protein abundance between CDH and control lungs, and with the comparable staining for TTF1 that has been observed previously [44]. …”

Section: Discussionsupporting

confidence: 61%

Surfactant Maturation Is Not Delayed in Human Fetuses with Diaphragmatic Hernia

et al. 2007

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BackgroundPulmonary hypoplasia and persistent pulmonary hypertension account for significant mortality and morbidity in neonates with congenital diaphragmatic hernia (CDH). Global lung immaturity and studies in animal models suggest the presence of surfactant deficiency that may further complicate the pathophysiology of CDH. However, data about surfactant status in human fetuses with CDH at birth are contradictory. The lack of a chronological study of surfactant content in late pregnancy has been a significant limitation. The appropriateness of administering surfactant supplements to neonates with CDH is therefore a debated question.Methods and FindingsWe investigated surfactant content in human fetuses with CDH compared to age-matched fetuses with nonpulmonary diseases used as controls. Concentrations of disaturated phosphatidylcholine and surfactant proteins were found to be similar at a given stage of pregnancy, with both components showing a similar pattern of increase with progressing pregnancy in fetuses with CDH and in control fetuses. Thyroid transcription factor 1, a critical regulator of surfactant protein transcription, similarly displayed no difference in abundance. Finally, we examined the expression of three glucocorticoid-regulated diffusible mediators involved in lung epithelial maturation, namely: keratinocyte growth factor (KGF), leptin, and neuregulin 1 beta 1 (NRG1-β1). KGF expression decreased slightly with time in control fetuses, but remained unchanged in fetuses with CDH. Leptin and NRG1-β1 similarly increased in late pregnancy in control and CDH lungs. These maturation factors were also determined in the sheep fetus with surgical diaphragmatic hernia, in which surfactant deficiency has been reported previously. In contrast to the findings in humans, surgical diaphragmatic hernia in the sheep fetus was associated with decreased KGF and neuregulin expression. Fetoscopic endoluminal tracheal occlusion performed in the sheep model to correct lung hypoplasia increased leptin expression, partially restored KGF expression, and fully restored neuregulin expression.ConclusionsOur results indicate that CDH does not impair surfactant storage in human fetuses. CDH lungs exhibited no trend toward a decrease in contents, or a delay in developmental changes for any of the studied surfactant components and surfactant maturation factors. Surfactant amounts are likely to be appropriate to lung size. These findings therefore do not support the use of surfactant therapy for infants with CDH. Moreover, they raise the question of the relevance of CDH animal models to explore lung biochemical maturity.

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Section: Discussionsupporting

confidence: 61%

Surfactant Maturation Is Not Delayed in Human Fetuses with Diaphragmatic Hernia

et al. 2007

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“…Deletion of Nxk2.1 in mice, the Titf1 knockout, causes severe thyroid and lung hypoplasia (Hösgör et al. ). In a broad review of lung development, Maeda et al.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary anatomy and a case of unilateral aplasia in a common snapping turtle (Chelydra serpentina): developmental perspectives on cryptodiran lungs

Schachner

Sedlmayr

Schott³

et al. 2017

Journal of Anatomy

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The common snapping turtle (Chelydra serpentina) is a well studied and broadly distributed member of Testudines; however, very little is known concerning developmental anomalies and soft tissue pathologies of turtles and other reptiles. Here, we present an unusual case of unilateral pulmonary aplasia, asymmetrical carapacial kyphosis, and mild scoliosis in a live adult C. serpentina. The detailed three-dimensional (3D) anatomy of the respiratory system in both the pathological and normal adult C. serpentina, and a hatchling are visualized using computed tomography (CT), microCT, and 3D digital anatomical models. In the pathological turtle, the right lung consists of an extrapulmonary bronchus that terminates in a blind stump with no lung present. The left lung is hyperinflated relative to the normal adult, occupying the extra coelomic space facilitated by the unusual mid-carapacial kyphotic bulge. The bronchial tree of the left lung retains the overall bauplan of the normal specimens, with some minor downstream variation in the number of secondary airways. The primary difference between the internal pulmonary structure of the pathological individual and that of a normal adult is a marked increase in the surface area and density of the parenchymal tissue originating from the secondary airways, a 14.3% increase in the surface area to volume ratio. Despite this, the aplasia has not had an impact upon the ability of the turtle to survive; however, it did interfere with aquatic locomotion and buoyancy control under water. This turtle represents a striking example of a non-fatal congenital defect and compensatory visceral hypertrophy.

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“…This work expands the impact of previous in vitro work by demonstrating potential feedback between these factors and Cldn6 availability in vivo. TTF-1 regulates target gene expression in concert with other gene regulatory factors to fine tune lung branching morphogenesis and to coordinate the expression of homeostatic proteins such as surfactant proteins (Boggaram, 2009;Bohinski et al, 1994;Hösgör et al, 2002). In addition, FoxA2 is required for normal airway epithelial differentiation and lung organogenesis (Wan et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Conditional pulmonary over-expression of Claudin 6 during embryogenesis delays lung morphogenesis

Jimenez

Belgique²,

Lewis³

et al. 2015

Int. J. Dev. Biol.

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Claudin 6 (Cldn6) is a tetraspanin protein expressed by barrier epithelial cells. In order to assess the effects of persistent tight junctions involving Cldn6 during lung development, a doxycycline (dox)-inducible conditional transgenic mouse was generated that up-regulates Cldn6 in the distal lung. Pups had unlimited access to dox from conception until sacrifice date at embryonic day (E) 18.5. Quantitative PCR, immunoblotting, and immunohistochemistry revealed significantly elevated Cldn6 expression in transgenic mice compared to non-transgenic controls. There were no differences in terms of lung size, lung weight, or whole body weight at the time of necropsy. Histological evaluations led to the discovery that E18.5 Cldn6 transgenic pups appeared to be in the early canalicular stage of development coincident with fewer, thickened respiratory airspaces. In contrast, controls appeared to have entered the saccular stage characterized by thin airspace walls and spherical architecture. Immunostaining for transcriptional regulators including TTF-1 and FoxA2 was conducted to assess cell differentiation and specific cell types were identified via staining for pro-surfactant protein C (alveolar type II epithelial cells) or Clara Cell Secretory Protein (cub or Clara cells). Lastly, cell turnover was qualitatively measured via staining for cell proliferation or apoptosis. These data suggest that Cldn6 is an important junctional protein potentially involved in the programming of epithelial cells during lung development. Furthermore, genetic down-regulation of Cldn6 as development proceeds may influence differentiation observed in the transition from the canalicular to the saccular lung. KEY WORDS: claudin 6, lung, transgenic, mouseLung development is a complex process of highly organized and dynamic events. Tubular branching of the lung airways characterizes the pseudoglandular stage of lung organogenesis and the subsequent canalicular stage coincides with pulmonary epithelial cell differentiation that results in the formation of the air-blood barrier (Burri, 1984;Torday, 1992;Copland and Post, 2004). Numerous signaling and transcriptional control pathways critically influence the precise deposition of specialized cell types along the proximaldistal pulmonary axis.Tight junctions (TJs) are increasingly recognized as potentially critical modulators spatial epithelial cell programming. TJs begin to form at cell-cell contacts as the respiratory epithelium develops into a complex monolayer (Crapo et al., 1983;Ward and Nicholas, 1984). TJs are critical in the developing lung as they provide the means of compartmentalization required of barrier derivation. TJs Int. J. Dev. Biol. 59: 479-485 (2015) doi: 10.1387/ijdb.150086pr Abbreviations used in this paper: CCSP, clara cell secretory protein; Cldn6, claudin 6; Dox, doxycycline; FoxA2, Forkhead Box A2; PCNA, proliferating cell nuclear antigen; SP-C, surfactant protein C; TJ, tight junction; TTF-1, thyroid transcription factor-1.are an assembly of resident integral prot...

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Thyroid transcription factor-1 expression during normal human lung development and in patients with congenital diaphragmatic hernia

Cited by 16 publications

References 18 publications

Surfactant Maturation Is Not Delayed in Human Fetuses with Diaphragmatic Hernia

Surfactant Maturation Is Not Delayed in Human Fetuses with Diaphragmatic Hernia

Pulmonary anatomy and a case of unilateral aplasia in a common snapping turtle (Chelydra serpentina): developmental perspectives on cryptodiran lungs

Conditional pulmonary over-expression of Claudin 6 during embryogenesis delays lung morphogenesis

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