Alterations in gene expression in T1 alpha null lung: a model of deficient alveolar sac development.
BACKGROUND
Development of lung alveolar sacs of normal structure and size at late gestation is necessary for the gas exchange process that sustains respiration at birth. Mice lacking the lung differentiation gene T1alpha [T1alpha(-/-)] fail to form expanded alveolar sacs, resulting in respiratory failure at birth. Since little is known about the molecular pathways driving alveolar sacculation, we used expression microarrays to identify genes altered in the abnormal lungs and, by inference, may play roles in normal lung morphogenesis.


RESULTS
Altered expression of genes related to cell-cell interaction, such as ephrinA3, are observed in T1alpha(-/-) at E18.5. At term, FosB, Egr1, MPK-1 and Nur77, which can function as negative regulators of the cell-cycle, are down-regulated. This is consistent with the hyperproliferation of peripheral lung cells in term T1alpha (-/-) lungs reported earlier. Biochemical assays show that neither PCNA nor p21 are altered at E18.5. At term in contrast, PCNA is increased, and p21 is decreased.


CONCLUSIONS
This global analysis has identified a number of candidate genes that are significantly altered in lungs in which sacculation is abnormal. Many genes identified were not previously associated with lung development and may participate in formation of alveolar sacs prenatally.
Millien
Guetchyn
G
Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA. gmillien@bu.edu
Spira
Avrum
A
Hinds
Anne
A
Wang
Junling
J
Williams
Mary C
MC
Ramirez
Maria I
MI
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D008168:Lung / Q000166:cytology / Q000196:embryology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D040081:Protein Array Analysis / Q000379:methods; D011650:Pulmonary Alveoli / Q000166:cytology / Q000196:embryology* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012131:Respiratory Insufficiency / Q000235:genetics / Q000473:pathology; D000098853:Podoplanin
D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C490441:Pdpn protein, mouse; D000098853:Podoplanin