Late gestational lung hypoplasia in a mouse model of the Smith-Lemli-Opitz syndrome.
BACKGROUND
Normal post-squalene cholesterol biosynthesis is important for mammalian embryonic development. Neonatal mice lacking functional dehydrocholesterol Delta7-reductase (Dhcr7), a model for the human disease of Smith-Lemli-Opitz syndrome, die within 24 hours of birth. Although they have a number of biochemical and structural abnormalities, one cause of death is from apparent respiratory failure due to developmental pulmonary abnormalities.


RESULTS
In this study, we characterized further the role of cholesterol deficiency in lung development of these mice. Significant growth retardation, beginning at E14.5 through E16.5, was observed in Dhcr7-/- embryos. Normal lobation but smaller lungs with a significant decrease in lung-to-body weight ratio was noted in Dhcr7-/- embryos, compared to controls. Lung branching morphogenesis was comparable between Dhcr7-/- and controls at early stages, but delayed saccular development was visible in all Dhcr7-/- embryos from E17.5 onwards. Impaired pre-alveolar development of varying severity, inhibited cell proliferation, delayed differentiation of type I alveolar epithelial cells (AECs) and delayed vascular development were all evident in knockout lungs. Differentiation of type II AECs was apparently normal as judged by surfactant protein (SP) mRNAs and SP-C immunostaining. A significant amount of cholesterol was detectable in knockout lungs, implicating some maternal transfer of cholesterol. No significant differences of the spatial-temporal localization of sonic hedgehog (Shh) or its downstream targets by immunohistochemistry were detected between knockout and wild-type lungs and Shh autoprocessing occurred normally in tissues from Dhcr7-/- embryos.


CONCLUSIONS
Our data indicated that cholesterol deficiency caused by Dhcr7 null was associated with a distinct lung saccular hypoplasia, characterized by failure to terminally differentiate alveolar sacs, a delayed differentiation of type I AECs and an immature vascular network at late gestational stages. The molecular mechanism of impaired lung development associated with sterol deficiency by Dhcr7 loss is still unknown, but these results do not support the involvement of dysregulated Shh-Patched-Gli pathway in causing this defect.
Yu
Hongwei
H
Division of Endocrinology, Diabetes and Medical Genetics, Medical University of South Carolina, STR 541, 114 Doughty Street, Charleston, SC 29403, USA. yuh@musc.edu
Wessels
Andy
A
Chen
Jianliang
J
Phelps
Aimee L
AL
Oatis
John
J
Tint
G Stephen
GS
Patel
Shailendra B
SB
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002784:Cholesterol / Q000172:deficiency; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000201:enzymology / Q000473:pathology; D004847:Epithelial Cells / Q000473:pathology; D005317:Fetal Growth Retardation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005865:Gestational Age; D053823:Hedgehog Proteins; D006801:Humans; D008168:Lung / Q000002:abnormalities* / Q000098:blood supply / Q000201:enzymology / Q000254:growth & development; D051379:Mice; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000172:deficiency / Q000235:genetics; D011650:Pulmonary Alveoli / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D019082:Smith-Lemli-Opitz Syndrome / Q000453:epidemiology / Q000235:genetics / Q000473:pathology*; D013261:Sterols / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics
D053823:Hedgehog Proteins; C509239:SHH protein, human; D013261:Sterols; D015534:Trans-Activators; D002784:Cholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase