Although there is accumulated evidence of a role for Notch in the developing lung, it is still unclear how disruption of Notch signaling affects lung progenitor cell fate and differentiation events in the airway epithelium. To address this issue, we inactivated Notch signaling conditionally in the endoderm using a Shh-Cre deleter mouse line and mice carrying floxed alleles of the Pofut1 gene, which encodes an O-fucosyltransferase essential for Notch-ligand binding. We also took the same conditional approach to inactivate expression of Rbpjk, which encodes the transcriptional effector of canonical Notch signaling. Strikingly, these mutants showed an almost identical lung phenotype characterized by an absence of secretory Clara cells without evidence of cell death, and showed airways populated essentially by ciliated cells, with an increase in neuroendocrine cells. This phenotype could be further replicated in cultured wild-type lungs by disrupting Notch signaling with a gamma-secretase inhibitor. Our data suggest that Notch acts when commitment to a ciliated or non-ciliated cell fate occurs in proximal progenitors, silencing the ciliated program in the cells that will continue to expand and differentiate into secretory cells. This mechanism may be crucial to define the balance of differentiated cell profiles in different generations of the developing airways. It might also be relevant to mediate the metaplastic changes in the respiratory epithelium that occur in pathological conditions, such as asthma and chronic obstructive pulmonary disease.
Maternal smoking is responsible for increased incidences of LBW and preterm delivery of babies, and therefore, smoking cessation/reduction should be advised to pregnant women to reduce morbidities in their neonates. Further studies are needed to clarify the correlation of fetal health with passive smoking, including exposure to environmental tobacco smoke and to other smokers in the family.
Improved compliance with handwashing was associated with a significant decrease in overall rates of nosocomial infection and respiratory infections in particular. Washing hands is a simple, economical, and effective method for preventing nosocomial infections in the NICU.
Little is known about the mechanisms by which the lung epithelial progenitors are initially patterned and how proximaldistal boundaries are established and maintained when the lung primordium forms and starts to branch. Here we identified a number of Notch pathway components in respiratory progenitors of the early lung, and we investigated the role of Notch in lung pattern formation. By preventing ␥-secretase cleavage of Notch receptors, we have disrupted global Notch signaling in the foregut and in the lung during the initial stages of murine lung morphogenesis. We demonstrate that Notch signaling is not necessary for lung bud initiation; however, Notch is required to maintain a balance of proximal-distal cell fates at these early stages. Disruption of Notch signaling dramatically expands the population of distal progenitors, altering morphogenetic boundaries and preventing formation of proximal structures. Our data suggest a novel mechanism in which Notch and fibroblast growth factor signaling interact to control the proximaldistal pattern of forming airways in the mammalian lung.The mammalian respiratory system arises from the ventral foregut endoderm. Studies in mice show that at around embryonic day 9 (E9) 2 respiratory progenitors are collectively identified in the ventral foregut as a group of endodermal cells expressing Titf1 (thyroid transcription factor-1, or Nkx2.1). Besides being the earliest known marker of respiratory progenitors, Titf1 appears to be required to regulate lung epithelial cell fate (1). By E9.5, major morphogenetic changes occur in the respiratory field, leading to Fgf10 (fibroblast growth factor 10)-mediated expansion of these progenitors to form the lung primordia. Once primary lung buds have formed, lateral buds arise at stereotyped positions from these tubules (the main bronchi) and undergo branching morphogenesis and differentiation to give rise to the bronchial tree (2, 3).Little is known about the mechanisms by which the lung epithelial progenitors are expanded and patterned into proximal and distal compartments during the early stages of lung morphogenesis. Furthermore, it is still unclear how proximaldistal boundaries are established and maintained when lung epithelial buds form and start to branch. Studies in other foregut derivatives, such as the pancreas and stomach implicate signaling by Notch as a critical regulator of pattern during organ formation (4, 5).The Notch pathway orchestrates a highly evolutionarily conserved mechanism of control of cell fate decisions, which plays a prominent role in establishing asymmetries or differences in signaling between two cells. During development, Notch-mediated mechanisms give rise to cellular diversity while also serving to generate compartments and to establish tissue boundaries (6 -8). Notch signaling results from cell-cell contact via interactions of Notch receptors (in mammalians, Notch1 to -4) with ligands (Delta-like 1, 3, and 4 and Jagged1 and -2) in adjacent cells. Ligand-receptor engagement results in shedding of the Not...
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