Pulmonary Developmental Biology

Introduction

A major impetus for the study of the developmental biology of the lung is the hope that it will shed light on pathways important to lung repair and regeneration, as well as on the causes of congenital lung and airway abnormalities.  The uses of targeted gene manipulations particularly in transgenic mice (1) have made major contributions to our understanding of early lung development (2) and to gene-environment interaction in a large variety of pathophysiologic perturbations relevant throughout prenatal and postnatal lung development. Conditional gene expression studies that can restrict altered expression to the lung at varying stages of development (3) have been at the forefront of discovering the molecular pathways responsible for specifying proximal and distal airways, (4) the differentiation of alveoli, and the cell-cell interactions responsible for alveolar repair and re-growth (5).  More recently, a number of investigators have focused on the identification and function of specialized cells that may be recruited to the lung from the circulation in order to take part in alveolar regeneration, so-called mesenchymal stem cells (6, 7).  Although the use of mouse models has been very helpful to identify pathways and mechanisms important to airway and alveolar development, it is important to recognize that there are significant species differences that limit the relevance of these model systems and the mouse-related websites (8). 

The main focus of this review was on websites that dealt with developmental biology in general, since a number of pathways relevant to branching morphogenesis, epithelial-mesenchymal reciprocal signaling, and other themes would have relevance to the pathways that organize lung development and repair.The search strategy hit only a few websites specifically aimed at lung development.

Search

1) Developmental Biology, General

Using Google™ to search the terms “developmental biology” and “resource” yielded over 900,000 hits.  Using “developmental biology” and “web resource” yielded 791 hits.  Eliminating sites with the words “course,” “department,” and “seminar” using Google’s Advanced Search improved the pool of relevant sites.  Using the search terms “developmental biology” and “web-based resource” further restricted the number of sites to about 100 sites, the most relevant of which were not aimed at mammalian species.

2) Developmental Biology, Pulmonary

Entering "lung developmental biology" as the search term in Google produced 126 hits in English, virtually all of which were sites related to individual researchers’ programs, rather than web utilities, with the same result entering “pulmonary developmental biology.” Entering “lung” and “developmental biology” returned 68,000 hits in English when the domain “*.edu” was specified using the Advanced Search Strategy.  Entering either search string above and specifying the domain using “*.gov” but excluding the words “entrez” and “PubMed” filtered out publications, and produced 1,390 hits, nearly all of which specified individual program announcements or intramural programs at the NIH NHLBI.

Best Websites

Jackson Laboratories Research Models

This site maintained by Jackson Laboratories links the gene, the locus, the phenotype and links to genetic databases in a very large data base of transgenic/knockout mice.The site is linked to dozens of other useful sites related to mouse genetic models.

1. Authority: The site is maintained by a premier supplier and developer of transgenic mice. Rating: 5

2. Currency: Frequently updated. Last update 14 days before this review was written. Rating: 5

3. Accuracy: The information was accurate and fairly complete. Rating: 5

4. Navigation & Readability: Thoughtful layout with immediate presentation of the phenotype and references, as well as gene symbols and accession numbers. Rating: 5

5. Utility: The strains identified by search parameters are limited to those provided by JAX Mice. Rating: 4

Summary: This will also be a “must have” site for pulmonary biology researchers that lists a number of categories of disrupted development and relevant mouse strains for modeling human disease.

Society for Developmental Biology

This is a handy clearinghouse that lists links to frequently used organisms and many of the sites reviewed here, as well as helpful links to atlases, genome sites, etc.

1. Authority: Maintained by the Society for Developmental Biology. Rating: 5

2. Currency: Frequently updated. Rating: 5

3. Accuracy: Accurate. Rating: 5

4. Navigation & Readability: Very easy to navigate with simple interface. Rating: 5

5. Utility: No limitations identified, nearly all links functional. Rating: 5

Summary: Definitely should be bookmarked.

Ancora

Site focused on study of highly conserved noncoding elements in metazoan genomes associated with developmental regulatory genes. The database is compatible with viewing in Ensembl.

1. Authority: Maintained by Boris Lenhard’s research group at the Bergen Center for Computational Science and by Par Engstrom at the European Bioinformatics Institute. Rating: 4

2. Currency: Last updated November 2008. Rating: 5

3. Accuracy: New site with frequent updating. Rating: 5

4. Navigation & Readability: Easy to navigate, but the color scheme is low contrast. Rating: 3

5. Utility: Interactive with users’ own sequence information, annotations. Rating: 5

Summary: Indispensable to genetics investigators focused on development.

Madame Curie Bioscience Database

Commercial database provides (for individual or institutional subscribers) online access to chapters from scientific books published by Landes.

1. Authority: Variable, depending on the book chapter identified by the search engine. Rating: 4

2. Currency: Because it accesses published books, it is necessarily less current than a database linked to recent journal articles. Rating: 3

3. Accuracy: The accuracy will depend on the accuracy of the books from which the chapters were drawn. The few chapters reviewed appeared accurate. Rating: 4

4. Navigation & Readability: The site is well organized. Rating: 4

5. Utility: Useful for the beginning investigator who wishes to identify scientific books that deal with topics broadly related to developmental biology. Searching “lung development” yielded seven chapters from books directly related to pulmonary developmental biology. Rating: 3

Summary: Helpful to determine the state of the art for beginners needing broad survey materials or compendia of methodology, but necessarily less current than peer-reviewed scientific literature.

Deltagen and Lexicon Knockout Mice and Phenotypic Data

The ‘parent’ site is essentially a shell that links to the information page describing the "Knockout Mouse Program (KOMP)" program and to the Jackson Laboratories-maintained MGI site.

1. Authority: The data are from the vendors or from the NIH. Rating: 5

2. Currency: The site is updated continually. Rating: 5

3. Accuracy: The data were accurate. Rating: 3

4. Navigation & Readability: Lots of text and would benefit by an outline style. Rating: 3

5. Utility: This site lists additional mouse models and is linked to other important resources of use to pulmonary developmental biology researchers. Rating: 3

Summary: This site will allow investigators to identify the phenotype of the listed gene knockouts.

EMAP Edinburgh Mouse Atlas Project

One search engine “EMAGE Gene Expression Database” localizes a number of genes expressed at varying stages of mouse embryonic development. Images displaying in situ hybridization signals for various genes are linked in HTML tables with gene symbols, genome location and gene accession number. A second utility, “The 3-D Embryo Atlas” provides a pictorial display of sagittal images taken through mouse wholemounts, allowing the viewer to click on the image to link to a stack of files that can then be displayed in higher resolution in any user-chosen plane of section.

1. Authority: This site is maintained by the University of Edinburgh. Rating: 4

2. Currency: The site lists 2008 as the last update. Rating: 4

3. Accuracy: Spatial annotations made public when the material submitted directly by investigators is published. Rating: 4

4. Navigation & Readability: In general the site is easy to navigate. It will take some effort to fully exploit the Java or web-based EMAGE Database, to display embryo images. This should only be attempted with a modern computer which runs an up-to-date browser that is Java-enabled. Rating: 4

5. Utility: It links in situ hybridization signal in images from embryos with gene symbols, genome location and gene accession number. The embryo anatomic display is unique. The site links to a number of database sites for biological imaging, gene expression and anatomy. Rating: 4

Summary: Unique site displaying detailed whole mount in situ hybridization images. Supposedly the site was designed to be updated by users but it only lists 2008 as the last update.

NHLBI Genetically Altered Animal Models

This site appears under "Information for Researchers/Other Online Resources" on the NIH NHLBI website, and allows the viewer to select a disease or pathophysiologic category from one drop-down menu, which then elicits a list of animal models linked with that category. A gene may also be selected that links with a disease or condition.

1. Authority: This site is maintained by NIH-NHBLI. Rating: 5

2. Currency: The site listed 8/28/2008 as the last update, and is reportedly updated every 6 months following PubMed search for relevant models and internal review of the publications by NHLBI scientific staff. However, a search of the reported pathways yields few recent model additions. Rating: 3

3. Accuracy: The list appears to be accurate, but the number of genes identified for a condition can be limited. For example, one category, “alveogenesis; lung development” only produced one model, while a similar category, “alveolar morphogenesis, alveolarization” also yielded only a single model, whereas several model systems have been reported which can impair alveolar development. Rating: 3

4. Navigation & Readability: Easy to navigate. Rating: 5

5. Utility: Features two drop-down menus that allow selection of a "condition" or a "gene" that is then linked to an animal model, usually a transgenic/knockout mouse. Selection of an entry in one category, e.g., “condition,” specifies the linked genes and provides a link to the published abstract in PubMed. Rating: 4

Summary: This site is well-designed, and very easy to use but some categories do not appear to be maintained with up-to-date information which limits the usefulness. If the gene is chosen, rather than the condition, the results are more complete.

Other Important Sites

• Embryology.ch
  http://www.embryology.ch/indexen.html

  Operated under the aegis of the Swiss Virtual Campus, a cooperative online embryology course. A joint effort of the Universities of Fribourg, Lausanne and Berne. Chapter on lung embryology has cited references, and descriptions of disruptions in lung development, aimed at medical students.

• The Virtual Embryo Project (v-Embryo (TM)).
  http://www.epa.gov/ncct/v-Embryo/approaches.html

  New EPA site focused on computational framework of developmental toxicity with links to bioinformatics sites.

Disclaimer

The author has no personal or financial interest in any of the websites discussed above. The author has no personal or financial interest in any of the websites discussed above. The author has no personal or financial interest in any of the websites discussed above.

References

1. Glasser SW, Korfhagen TR, Wert SE, Whitsett JA. Transgenic models for study of pulmonary development and disease. Am J Physiol 1994; 267:L489-L497.
2. Cardoso WV, Lu J. Regulation of early lung morphogenesis: questions, facts and controversies. Development 2006;133:1611-1624.
3. Perl AK, Wert SE, Loudy DE, Shan Z, Blair PA, Whitsett JA. Conditional recombination reveals distinct subsets of epithelial cells in trachea, bronchi, and alveoli. Am J Respir Cell Mol Biol 2005;33:455-462.
4. Liu Y, Jiang H, Crawford HC, Hogan BL. Role for ETS domain transcription factors Pea3/Erm in mouse lung development. Dev Biol 2003;261:10-24.
5. Rawlins EL, Hogan BL. Epithelial stem cells of the lung: privileged few or opportunities for many? Development 2006;133:2455-2465.
6. Rawlins EL, Hogan BL. Ciliated epithelial lifespan in the mouse trachea and lung. Am J Physiol Lung Cell Mol Physiol 2008;295:L231-J234.
7. Wenzel S, Holgate MT. The mouse trap: It still yields few answers in asthma. Am J Respir Crit Care Med. 2006;174:1173-1176.