Hydroxysteroid (17beta) dehydrogenase 7 activity is essential for fetal de novo cholesterol synthesis and for neuroectodermal survival and cardiovascular differentiation in early mouse embryos.
Hydroxysteroid (17beta) dehydrogenase 7 (HSD17B7) has been shown to catalyze the conversion of both estrone to estradiol (17-ketosteroid reductase activity) and zymosterone to zymosterol (3-ketosteroid reductase activity involved in cholesterol biosynthesis) in vitro. To define the metabolic role of the enzyme in vivo, we generated knockout mice deficient in the enzyme activity (HSD17B7KO). The data showed that the lack of HSD17B7 results in a blockage in the de novo cholesterol biosynthesis in mouse embryos in vivo, and HSD17BKO embryos die at embryonic day (E) 10.5. Analysis of neural structures revealed a defect in the development of hemispheres of the front brain with an increased apoptosis in the neuronal tissues. Morphological defects in the cardiovascular system were also observed from E9.5 onward. Mesodermal, endodermal, and hematopoietic cells were all detected by the histological analysis of the visceral yolk sac, whereas no organized vessels were observed in the knockout yolk sac. Immunohistological staining for platelet endothelial cell adhesion molecule-1 indicated that the complexity of the vasculature also was reduced in the HSD17B7KO embryos, particularly in the head capillary plexus and branchial arches. At E8.5-9.5, the heart development and the looping of the heart appeared to be normal in the HSD17B7KO embryos. However, at E10.5 the heart was dilated, and the thickness of the cardiac muscle and pericardium in the HSD17B7KO embryos was markedly reduced, and immunohistochemical staining for GATA-4 revealed that HSD17B7KO embryos had a reduced number of myocardial cells. The septum of the atrium was also defected in the knockout mice.
Jokela
Heli
H
Department of Physiology, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland.
Rantakari
Pia
P
Lamminen
Tarja
T
Strauss
Leena
L
Ola
Roxana
R
Mutka
Aino-Liisa
AL
Gylling
Helena
H
Miettinen
Tatu
T
Pakarinen
Pirjo
P
Sainio
Kirsi
K
Poutanen
Matti
M
D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001808:Blood Vessels / Q000196:embryology / Q000201:enzymology; D002454:Cell Differentiation / Q000235:genetics*; D002784:Cholesterol / Q000096:biosynthesis*; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology; D054258:Neural Plate / Q000196:embryology* / Q000201:enzymology; D015017:Yolk Sac / Q000098:blood supply / Q000196:embryology
D002784:Cholesterol; D015067:17-Hydroxysteroid Dehydrogenases; C532640:PRAP protein, mouse