Lung Development and Disease

Dr Charlotte Dean, Head of group

Our group is seeking to understand the cellular and molecular events underlying lung development.

The lung develops by a process known as branching morphogenesis from a simple bud into a complex tree-like structure comprised of several differentiated cell types that facilitate efficient gas/air exchange.

Moreover, there are many parallels between lung development and certain hallmarks of some lung diseases such as airway re-modelling in asthma and the abnormal wound healing response that can lead to fibrosis. Using the tools and techniques of developmental and cell biology, combined with in vivo lung function testing, we seek to broaden our understanding of the mechanisms underlying lung disease using a variety of mouse and human model systems.

Current projects:

We are studying three broad categories of mouse mutants as tools to broaden our understanding of lung disease pathobiology.

Models with abnormal lung development - recent work has focused on the role of the Planar polarity (PCP) pathway in lung development. We have identified a role for a number of genes from the PCP pathway in lung development. PCP mouse mutants all exhibit abnormal lung development including reduced numbers of epithelial branches, abnormally shaped lung lobes and aberrant cytoskeletal organization. We are currently undertaking further detailed studies of the role of this pathway in the lung.

Mouse models of candidate human asthma susceptibility genes - We are investigating both point mutants and null mutants of human asthma associated genes in the mouse. This work will enable us to confirm the identity of asthma susceptibility genes identified in human GWAS studies and to elucidate gene function (collaboration with Professors, Lloyd, Moffatt and Cookson and Dr Zhang, NHLI).
 
Models of age-related respiratory disease - As part of the ENU ageing screen currently running at MRC Harwell, we are phenotyping mice for age-related susceptibility to infection and lung function deficits in order to identify novel mouse models of age-related respiratory disease (collaboration with Professors Lloyd and Hussell)

Selected Publications

Yates, L.L., Papakrivopoulou, J., Long, D., Goggolidou, P., Connolly, J., Woolf, A. and Dean C.H. (2010)
The planar cell polarity gene Vangl2 is required for mammalian kidney branching morphogenesis and glomerular maturation. Hum. Mol. Genet. 19(23):4663-76.

Paudyal A, Damrau C, Patterson VL, Ermakov A, Formstone C, Lalanne Z, Wells S, Lu X, Norris DP, Dean CH, Henderson DJ, Murdoch JN (2010).
The novel mouse mutant, chuzhoi, has disruption of Ptk7 protein and exhibits defects in neural tube, heart and lung development and abnormal planar cell polarity in the ear. BMC Dev Biol. 2010 Aug 12;10:87.

Yates, L.L., Schnatwinkel, C., Murdoch J.N., Bogani D., Formstone, C.J., Townsend, S., Greenfield, A., Niswander, L.A. and Dean, C.H. (2010)
The PCP genes Celsr1 and Vangl2 are required for normal lung branching morphogenesis. Hum. Mol. Genet. 19(11):2251-67.

Yates L.L, McMurray F., Zhang Y., Greenfield A., Moffatt M.F., Cookson W.O. and Dean C.H. (2009) ENU mutagenesis as a tool for understanding lung development and disease Biochem. Soc. Trans., 37 (4):838-42.