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1. Development Publication: This study shows by genetic and pharmacological approaches that endogenous activation of Notch3 signaling selectively controls the pool of undifferentiated progenitors of upper airways available for differentiation.

Notch3-Jagged signaling controls the pool of undifferentiated airway progenitors. (Mori et al, Development, 2015 Jan 15;142(2):258-67. doi: 10.1242/dev.116855. PMID: 25564622).

 
2. Developmental Cell Publication: This work shows that Hippo-Yap is crucial for formation of airways during lung development and for differentiation of adult airway progenitors

The Hippo Pathway Effector Yap Controls Patterning and Differentiation of Airway Epithelial Progenitors (Mahoney et al. Dev Cell. 2014 Jul 28;30:137-50.) See also comment in Rock JR. Dev Cell. 2014 Jul 28;30:112-4.
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The transcriptional co-activator Yes-associated protein (Yap) and its regulation by Hippo pathway kinases play a key role in controlling expansion and differentiation of stem cell pools in multiple organs. Hyperactive Yap is present in cancer of various origins, including the lung. Less is known about the role of Hippo-Yap in lung development and homeostasis.

In this paper Mahoney et al. show that Yap is crucial to initiate a developmental program that ultimately generates the airways in the lung. Mutant mice lacking Yap form the distal lung compartment, but not the airways. Interestingly, when epithelial tubules are forming and branching, a nucleocytoplasmic shift of Yap marks the boundary between the progenitors of the distal lung and the airway compartment. At this transition zone, Yap specifies a transcriptional program that controls Sox2 expression, enabling the initiation of the airway progenitor cell program. Without Yap, epithelial progenitors are unable to properly respond to local cues, such as TGF beta and properly induce Sox2 to form airways. Moreover, Yap phosphorylation is critical for secretory and ciliated cell differentiation in airways later in development and in adult life.

These studies reveal a role for Hippo-Yap in integrating growth factor-induced cues in the developing and adult progenitors likely to be also key in regeneration-repair.  See also comment in Preview (Sizing up lung stem cells. Rock JR. Dev Cell. 2014 Jul 28;30:112-4).

 
3. PLoS One Publication:  The study identifies candidate markers of secretory (Clara or Club, CC) cells and their precursors and provides evidence that CC heterogeneity occurs already during embryonic development.

Analysis of Notch signaling-dependent gene expression in developing airways reveals diversity of Clara cells (Guha  et al. PLoS One. 2014 Feb 21;9(2):e88848).
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Clara cells (Club cells, CCs) are a heterogeneous population of secretory cells that play an essential role in airway homeostasis and in post-injury repair as facultative progenitors of the airway epithelium. Analysis of the extent and origin of CC diversity is limited by knowledge of genes expressed in these cells and their precursors. To address this issue, global gene expression analysis and subsequent characterization of expression patterns were conducted in the embryonic lungs of wild type and Notch deficient mice (Rbpjkcnull), in which CC do not form. This identified regional expression of a number of genes in CC precursors. Notably, Reg3g, Chad, Gabrp and Lrrc26 were enriched in proximal airways, while Hp labeled CCs in the distal airways, and Upk3a was found in clusters of CC precursors surrounding neuroepithelial bodies. Seven of the eleven genes identified, including Reg3g, Hp, and Upk3a, were expressed in the adult CCs in a pattern similar to that observed in the developing airway. The data support the idea that diversification of the CC phenotype occurs already during embryonic development
 
4. JCI Publication: Chen and colleagues provide novel evidence that prenatal disruption of RA signaling results in aberrant overly differentiated smooth muscle in airways.  The study uncovers a previously unsuspected role of RA signaling in preventing excessive smooth muscle formation when airways are developing.

Prenatal retinoid deficiency leads to airway hyperresponsiveness in adult mice
(Chen et al. J Clin Invest. 2014 Feb 3;124(2):801-11. doi: 10.1172/JCI70291)
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Vitamin A and its active metabolite retinoic acid (RA) are essential for lung formation, however little is known about how prenatal Vitamin A deficiency influences postnatal lung function. Using genetic, pharmacological and dietary of models of RA deficiency in mice, Chen and colleagues provide novel evidence that prenatal disruption of RA signaling results in aberrant overly differentiated smooth muscle in airways. The defect persists postnatally regardless of the adult vitamin A status and is recognized by airway hyperresponsiveness and structural changes in the bronchial smooth muscle. The study uncovers a previously unsuspected role of RA signaling in preventing excessive smooth muscle formation when airways are developing.
 
5. Methods Mol. Biol. Publication: How to make lungs out of embryonic foreguts.

Culture of mouse embryonic foregut explants (Chen and Cardoso. Methods Mol Biol, 2014,Vol.1189,p.163-169).
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The ability to culture embryonic organ rudiments and follow their development ex vivo has helped to understand how tissues are constructed and what cellular and biological events are important in this process. Here we outline a technique for isolation and ex vivo growth of foregut explants from E8.5 mouse embryos. This technique serves as a reliable tool for the analysis of the morphogenetic processes and signaling networks during early development of foregut derivatives, such as the lungs

Press Releases
 

Chen et al. JCI 2014

Videos
JCI 2014: 'Prenatal retinoid deficiency leads to airway hyperresponsiveness in adult mice'
 

Tsao et al. Development 2009

Chen et al. Development 2007

 

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