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Workshop Summary

Am. J. Respir. Cell Mol. Biol. Vol. 25, pp. 137-140, 2001

Internet address: www.atsjournals.org

Basic Mechanisms of Lung Development

Eighth Woods Hole Conference on Lung Cell Biology 2000

Wellington V. Cardoso and Mary C. Williams

Pulmonary Center, Department of Medicine, Boston University, Boston, Massachusetts

Studies of the molecular regulation of lung development

have reached the log-growth phase. The key questions related

to lung development are formidable ones to answer,

demanding sophisticated and sensitive molecular tools and

the use of many different animal, organ, and cellular experimental

models. The eighth Y2K Woods Hole Conference

on Lung Cell Biology, organized by faculty of the Pulmonary

Center, Boston University School of Medicine, and

supported by the Division of Lung Diseases of the National

Heart, Lung, and Blood Institute, explored some of the recent

research in this basic area of lung cell and molecular biology.

Many of the fundamental questions, concepts, and

observations about basic developmental processes and lung

development have been addressed in recent reviews (1-10).

Fundamental Questions

The fundamental questions in lung development are interesting

but difficult to answer in specific molecular terms. Many,

if not all, of these questions apply to the development of

other organs and are not unique to lung development per se

or to the mammalian lung. For that reason a number of presentations

summarized the current molecular understanding

of model systems including chick limb, tracheal system of

Drosophila

, and organogenesis of the mammalian liver.

Other presentations described postnatal development because

it is well known that certain changes in lung structure

and function, such as alveolization, occur mainly after birth.

The key questions discussed at the meeting included

these: What directs an area of the foregut to become lung,

and what cellular and molecular mechanisms account for

initiation of budding to form the lung? What are the positive

and negative regulators of branching that result in

bronchial tree formation? What signaling pathways are involved,

and what target genes are activated or repressed to

initiate cell proliferation, differentiation, deposition of matrix,

and vasculogenesis of the lung? What are the regulatory

events that result in the proximal-to-distal patterns of

epithelial differentiation? What genes control airway and

alveolar dimensions? How is expression of important lung

genes specifically regulated? What are the developmental

and adult functions of proteins expressed solely and/or

mainly in the lung? How plastic is the phenotype of differentiated

lung cells, both in developing and adult lung?

It is clear that we have assembled lists of molecules that

appear to influence lung development, and other lists describing

changes in cellular, molecular, and organ phenotypes

due to manipulation of the amount, site, or timing of

expression of these molecules. However, we do not understand

well--if at all--the integrated regulatory pathways

that direct the complex processes that produce this highly

patterned, multicellular organ.

Initiation of Lung Bud Formation

What are the events, signaling pathways, and regulatory molecules

that initiate lung bud formation from the foregut in the

first place? The answer is not certain, although interfering with

expression of several molecules can prevent initiation. Studying

the formation of liver and pancreas, also foregut derivatives,

provides some insight into foregut specification. Direct

contact between cardiac mesoderm and foregut epithelium is

required for liver induction. Fibroblast growth factors (FGFs)

from the mesoderm, including FGF-1, -2, and -8, interact with

the endodermal FGF receptors, resulting in the binding to

their cognate

cis

-elements of factors that transactivate liver

genes, such as albumin,



-fetoprotein, and transthyretin.

The transcription factor pancreatic-duodenum homeobox

(PDX)-1 appears to distinguish between sites of liver and

pancreas induction. PDX-1 expression is inhibited by cardiac

mesoderm,