Abstract
To characterize temporal patterns of transcriptional activity during normal lung development, we generated genome wide gene expression data for 26 pre- and post-natal time points in three common inbred strains of laboratory mice (C57BL/6J, A/J, and C3H/HeJ). Using Principal Component Analysis and least squares regression modeling, we identified both strain-independent and strain-dependent patterns of gene expression. The 4,683 genes contributing to the strain-independent expression patterns were used to define a murine Developing Lung Characteristic Subtranscriptome (mDLCS). Regression modeling of the Principal Components supported the four canonical stages of mammalian embryonic lung development (embryonic, pseudoglandular, canalicular, saccular) defined previously by morphology and histology. For postnatal alveolar development, the regression model was consistent with four stages of alveolarization characterized by episodic transcriptional activity of genes related to pulmonary vascularization. Genes expressed in a strain-dependent manner were enriched for annotations related to neurogenesis, extracellular matrix organization, and Wnt signaling. Finally, a comparison of mouse and human transcriptomics from pre-natal stages of lung development revealed conservation of pathways associated with cell cycle, axon guidance, immune function, and metabolism as well as organism-specific expression of genes associated with extracellular matrix organization and protein modification. The mouse lung development transcriptome data generated for this study serves as a unique reference set to identify genes and pathways essential for normal mammalian lung development and for investigations into the developmental origins of respiratory disease and cancer. The gene expression data are available from the Gene Expression Omnibus (GEO) archive (GSE74243). Temporal expression patterns of mouse genes can be investigated using a study specific web resource (http://lungdevelopment.jax.org).
Highlights
Proper development of the mammalian respiratory system requires the spatiotemporal coordination of molecular interactions among more than 40 different cell types (Breeze & Wheeldon, 1977) to form a complex, highly branched structure and associated vasculature for facilitating gas-exchange
These analyses provide significant impact for both basic and translational research into mammalian lung development through the generation of a high-resolution molecular framework of murine lung development, comparative genomic analyses of human and mouse lung development, and the identification of putative pathways associated with respiratory pathology
The temporal expression pattern for PC1 divides the developmental timeline in two segments: (1) embryonic, pseudoglandular, and canalicular stages versus (2) saccular, alveolar, and mature stages
Summary
Proper development of the mammalian respiratory system requires the spatiotemporal coordination of molecular interactions among more than 40 different cell types (Breeze & Wheeldon, 1977) to form a complex, highly branched structure and associated vasculature for facilitating gas-exchange. There are differences between mouse and human lung anatomy and cell type distribution (Braun et al, 2012; Irvin & Bates, 2003; Keli, Mogha & Egan, 2010; Wright, Cosio & Churg, 2008), the basic morphological hallmarks of the developing lung are comparable between mouse and human (Rackley & Stripp, 2012) These conserved features make the laboratory mouse an invaluable model system for identifying and characterizing genes, pathways, and networks that are fundamental to normal lung development and disease in humans (Dutt & Wong, 2006; Moore et al, 2013; Rawlins & Perl, 2012; Wright, Cosio & Churg, 2008). The canalicular stage (CAN) follows the formation of the terminal bronchioles of the five lung lobes This stage is defined by expansion of the canaliculi, which form the pulmonary parenchyma, and concurrent expansion of the surrounding capillary network. Expansion of the capillary bed continues during this stage, along with pulmonary innervation and establishment of the lymphatic network (Schraufnagel, 2010)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
