UNSW Embryology

Respiratory Molecular Development

© Dr Mark Hill (2008)

Acknowledgements

Introduction

The respiratory system does not carry out its physiological function (of gas exchange) until after birth. The respiratory tract, diaphragm and lungs do form early in embryonic development.

In the head/neck region, the pharynx forms a major arched cavity within the phrayngeal arches.

The lungs go through 4 distinct phases of development (5-17 week pseudoglandular, 16-25 week canalicular, 24-40 week terminal sac, late fetal-8years alveolar)

Late in fetal development respiratory motions and amniotic fliud are thought to have a role in lung maturation.

Development of this system is not completed until the last weeks of Fetal development, just before birth. Therefore premature babies have difficulties associated with insufficient surfactant (end month 6 alveolar cells type 2 appear and begin to secrete surfactant).

Page Links: Introduction | Some Recent Findings | Molecules | References | Glossary

Some Recent Findings

Ross J. Metzger, Ophir D. Klein, Gail R. Martin, Mark A. Krasnow The branching programme of mouse lung development Nature 453, 745-750 (5 June 2008) doi:10.1038/nature07005

"we present the complete three-dimensional branching pattern and lineage of the mouse bronchial tree, reconstructed from an analysis of hundreds of developmental intermediates. ...propose that each mode of branching is controlled by a genetically encoded subroutine, a series of local patterning and morphogenesis operations, which are themselves controlled by a more global master routine."

Ackerman KG, Wang J, Luo L, Fujiwara Y, Orkin SH, Beier DR. Gata4 is necessary for normal pulmonary lobar development. Am J Respir Cell Mol Biol. 2007 Apr;36(4):391-7.

"...we have found that a Fog2-Gata4 interaction is critical for the development of normal pulmonary lobar structure, and this phenotype is not influenced by the additional loss of Gata6 interaction. Fog2 and Gata4 in the early pulmonary mesenchyme participate in patterning the secondary bronchus of the accessory lobe."

Shu W, Lu MM, Zhang Y, Tucker PW, Zhou D, Morrisey EE. Foxp2 and Foxp1 cooperatively regulate lung and esophagus development. Development. 2007 May;134(10):1991-2000.

"The airways of the lung develop through a reiterative process of branching morphogenesis that gives rise to the intricate and extensive surface area required for postnatal respiration. The forkhead transcription factors Foxp2 and Foxp1 are expressed in multiple foregut-derived tissues including the lung and intestine. ...loss of Foxp2 in mouse leads to defective postnatal lung alveolarization, contributing to postnatal lethality."

Harris KS, Zhang Z, McManus MT, Harfe BD, Sun X. Dicer function is essential for lung epithelium morphogenesis. Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2208-13.

"DICER is a key enzyme that processes microRNA and small interfering RNA precursors into their short mature forms, enabling them to regulate gene expression. Only a single Dicer gene exists in the mouse genome, and it is broadly expressed in developing tissues. Dicer-null mutants die before gastrulation.......leading us to propose that Dicer plays a specific role in regulating lung epithelial morphogenesis independent of its requirement in cell survival."

Kumar VH, Lakshminrusimha S, Abiad MT, Chess PR, Ryan RM. Growth factors in lung development. Adv Clin Chem. 2005;40:261-316. "...Lung bud formation, cell differentiation, and its interaction with the splanchnic mesoderm are regulated by HNF-3beta, Shh, Nkx2.1, HNF-3/Forkhead homolog-8 (HFH-8), Gli, and GATA transcription factors. HNF-3beta regulates Nkx2.1, a transcription factor critical to the formation of distal pulmonary structures. Nkx2.1 regulates surfactant protein genes that are important for the development of alveolar stability at birth. Shh, produced by the foregut endoderm, regulates lung morphogenesis signaling through Gli genes expressed in the mesenchyme. FGF10, produced by the mesoderm, regulates branching morphogenesis via its receptors on the lung epithelium. Alveolization and formation of the capillary network are influenced by various factors that include PDGF, vascular endothelial growth factor (VEGF), and retinoic acid."

Molecules

Below is a selection of some molecules showing association with lung development.

A Disintegrin And Metalloprotease (ADAM33) membrane-anchored metalloprotease, occurs in human embryonic bronchi and surrounding mesenchyme. Model suggests that ADAM activated by several G protein-coupled receptors agonists, producing a mature EGFR ligand, leading to EGFR transactivation.

Aquaporins molecular water channels

Bone morphogenetic protein (BMP)

Coiled-coil-DIX1 (Ccd1) forms homomeric and heteromeric complexes with Dishevelled and Axin, and positively regulates the Wnt/beta-catenin pathway. Expressed in mouse lung bud (E12.5-E14.5) and bronchial epithelium (E17.5).

Dicer enzyme that processes microRNA and small interfering RNA precursors into their short mature forms.

Epidermal growth factor receptor (EGFR)

gene mutation present in some lung adenocarcinomas.

expression reduced in fetal hypoplastic lungs.

Fibroblast Growth Factor 9 (FGF9)

signals from mesothelium (future pleura) to sub-mesothelial mesenchyme through both FGFR1 and FGFR2 to induce proliferation.

signals from the epithelium to the sub-epithelial mesenchyme to maintain SHH signaling

Friend of Gata 2 (Fog2) (Zfpm2) required for diaphragm and lung development.

Glucocorticoids (GC) regulate branching morphogenesis and cytodifferentiation in developing lung.

Ly6/neurotoxin-1 (lynx1) (OMIM - LYNX1)

nAChR modulator protein in nicotinic neurons

expressed after 71 days in fetal lungs and increased with age

increased lung expression following prenatal nicotine exposure

Late-gestation lung protein 1 (LGL1) fetal lung mesenchyme a secreted glycoprotein that stimulates branching morphogenesis of the developing lung bud. (PMID: 17670908)

Midkine (MK) small protein has a role in epithelial mesenchymal interactions during organogenesis (Protein-tyrosine phosphatase zeta (PTPzeta) is MK receptor).

Phosphatidylcholine (PC) surfactant which increases in late fetal lung.

Plasmalemma vesicle protein-1 (PV-1) caveolae-associated protein expressed developmentally regulated in the rat lung endothelial cells.

Plexins family of transmembrane protein receptors for semaphorins (Plexin-A1 has a role in lung morphogenesis).

Retinoic Acid (RA) regulate branching morphogenesis and cytodifferentiation in developing lung.

Senescence marker protein-30 (SMP30) multifunctional protein can protect cellular functions from age-associated deterioration. Mouse KO model available, potentially for study of age-related lung diseases, including cigarette smoke-induced pulmonary emphysema.

Sonic Hedgehog (SHH)

Surfactant, pulmonary-associated protein C (SFTPC) peptide secreted by the alveolar type II pneumocytes of the lung.

Vascular Endothelial Growth Factor (VEGF) alveolization and formation of lung capillary network.

Wnt

(some molecules text modified abstracts from References listed below)

References

Borok Z, Li C, Liebler J, Aghamohammadi N, Londhe VA, Minoo P. Developmental pathways and specification of intrapulmonary stem cells. Pediatr Res. 2006 Apr;59(4 Pt 2):84R-93R.

White AC, Xu J, Yin Y, Smith C, Schmid G, Ornitz DM. FGF9 and SHH signaling coordinate lung growth and development through regulation of distinct mesenchymal domains. Development. 2006 Apr;133(8):1507-17.

Soma K, Shiomi K, Keino-Masu K, Masu M. Expression of mouse Coiled-coil-DIX1 (Ccd1), a positive regulator of Wnt signaling, during embryonic development. Gene Expr Patterns. 2006 Mar;6(3):325-30.

Hooper SB, Wallace MJ. Role of the physicochemical environment in lung development. Clin Exp Pharmacol Physiol. 2006 Mar;33(3):273-9.

Warburton D, Bellusci S, De Langhe S, Del Moral PM, Fleury V, Mailleux A, Tefft D, Unbekandt M, Wang K, Shi W.    [See Related Articles] Molecular mechanisms of early lung specification and branching morphogenesis. Pediatr Res. 2005 May;57(5 Pt 2):26R-37R.

Ackerman KG, Herron BJ, Vargas SO, Huang H, Tevosian SG, Kochilas L, Rao C, Pober BR, Babiuk RP, Epstein JA, Greer JJ, Beier DR. Fog2 is required for normal diaphragm and lung development in mice and humans. PLoS Genet. 2005 Jul;1(1):58-65.

Kumar VH, Lakshminrusimha S, Abiad MT, Chess PR, Ryan RM.    [See Related Articles] Growth factors in lung development. Adv Clin Chem. 2005;40:261-316. Review.

Groenman F, Unger S, Post M.    [See Related Articles] The molecular basis for abnormal human lung development. Biol Neonate. 2005;87(3):164-77. Epub 2004 Dec 9. Review.

Liu H, Wintour EM. Aquaporins in development -- a review. Reprod Biol Endocrinol. 2005 May 11;3(1):18.

Haitchi HM, Powell RM, Shaw TJ, Howarth PH, Wilson SJ, Wilson DI, Holgate ST, Davies DE. ADAM33 expression in asthmatic airways and human embryonic lungs. Am J Respir Crit Care Med. 2005 May 1;171(9):958-65.

Sekhon HS, Song P, Jia Y, Lindstrom J, Spindel ER. Expression of lynx1 in developing lung and its modulation by prenatal nicotine exposure. Cell Tissue Res. 2005 May;320(2):287-97.

Hnasko R, Ben-Jonathan N. Developmental regulation of PV-1 in rat lung: association with the nuclear envelope and limited colocalization with Cav-1. Am J Physiol Lung Cell Mol Physiol. 2005 Feb;288(2):L275-84.

Perala NM, Immonen T, Sariola H. The expression of plexins during mouse embryogenesis. Gene Expr Patterns. 2005 Feb;5(3):355-62.

Parera MC, van Dooren M, van Kempen M, de Krijger R, Grosveld F, Tibboel D, Rottier R. Distal angiogenesis: a new concept for lung vascular morphogenesis. Am J Physiol Lung Cell Mol Physiol. 2005 Jan;288(1):L141-9.

van Tuyl M, Liu J, Wang J, Kuliszewski M, Tibboel D, Post M. Role of oxygen and vascular development in epithelial branching morphogenesis of the developing mouse lung. Am J Physiol Lung Cell Mol Physiol. 2005 Jan;288(1):L167-78.

Rajatapiti P, Kester MH, de Krijger RR, Rottier R, Visser TJ, Tibboel D. Expression of glucocorticoid, retinoid, and thyroid hormone receptors during human lung development. J Clin Endocrinol Metab. 2005 Jul;90(7):4309-14.

Chinoy MR.    [See Related Articles] Lung growth and development. Front Biosci. 2003 Jan 1;8:d392-415. Review.

Chinoy MR, Chi X, Cilley RE. Down-regulation of regulatory proteins for differentiation and proliferation in murine fetal hypoplastic lungs: altered mesenchymal-epithelial interactions. Pediatr Pulmonol. 2001 Aug;32(2):129-41.

O'Rahilly R, Tucker JA.    [See Related Articles] The early development of the larynx in staged human embryos. I. Embryos of the first five weeks (to stage 15). Ann Otol Rhinol Laryngol. 1973 Sep-Oct;82:1-27.

Liu H, Wintour EM. Aquaporins in development -- a review. Reprod Biol Endocrinol. 2005 May 11;3(1):18.

Selected Lists of References from PubMed March 1999 search results are available for School of Anatomy computers without internet access. Computers with internet access can search from either Selected Research Articles and Reviews | Respiratory/development/review/5year limit" | "Lung development/review/5year limit"

Glossary of Terms

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Respiratory Terms

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