The purpose of this proposal is to better understand the role of cholesterol in normal embryonic development. The role of cholesterol has recently been highlighted by the discovery that mutations of the sterol delta-7 reductase (DHCR7), the last enzyme in the cholesterol biosynthesis pathway, cause the Smith-Lemli-Opitz Syndrome (SLOS, MIM 270400). SLOS is a relatively common multiple congenital abnormality syndrome, affecting embryonic development of brain, heart, limbs, intestine and lungs, as well as a number of other organs. Sterol delta-7 reductase is predicted to be a 9 transmembrane-domain spanning integral membrane protein localized to the endoplasmic reticulum and catalyzes the conversion of 7-dehydrocholesterol to cholesterol. Understanding the biology of cholesterol metabolism during embryonic development is therefore of some importance. In addition, understanding the molecular biology of sterol delta-7 reductase, how the mutations disrupt this enzyme and gaining a better understanding of this enzyme may allow us, in the future, to devise better strategies to treat patients with Smith-Lemli-Opitz syndrome. To accomplish this, we have combined the powerful approaches of genetics, animal models, and cell biology to elucidate structure-function and biological relationships. We have developed a mouse model for SLOS, using targeted disruption of the murine dhcr7 gene. We will use tissue-specific in vivo complementation to abrogate the neonatal lethality of the homozygous knock out mice. Additionally, molecular characterization of both the knockout mice, as well as our in vitro studies will help us better understand the mechanistic processes involved in both the pathogenesis of SLOS, as well as the normal role of cholesterol in embryogenesis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Metabolism Study Section (MET)
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Ershow, Abby
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Medical University of South Carolina
Internal Medicine/Medicine
Schools of Medicine
United States
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Tint, G S; Pan, Luxing; Shang, Quan et al. (2014) Desmosterol in brain is elevated because DHCR24 needs REST for Robust Expression but REST is poorly expressed. Dev Neurosci 36:132-42
Matabosch, Xavier; Rahman, Mahbuba; Hughes, Beverly et al. (2009) Steroid production and excretion by the pregnant mouse, particularly in relation to pregnancies with fetuses deficient in Delta7-sterol reductase (Dhcr7), the enzyme associated with Smith-Lemli-Opitz syndrome. J Steroid Biochem Mol Biol 116:61-70
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Yu, Hongwei; Li, Man; Tint, G Stephen et al. (2007) Selective reconstitution of liver cholesterol biosynthesis promotes lung maturation but does not prevent neonatal lethality in Dhcr7 null mice. BMC Dev Biol 7:27
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Yu, Hongwei; Wessels, Andy; Tint, G Stephen et al. (2005) Partial rescue of neonatal lethality of Dhcr7 null mice by a nestin promoter-driven DHCR7 transgene expression. Brain Res Dev Brain Res 156:46-60
Yu, Hongwei; Wessels, Andy; Chen, Jianliang et al. (2004) Late gestational lung hypoplasia in a mouse model of the Smith-Lemli-Opitz syndrome. BMC Dev Biol 4:1
Klett, Eric L; Patel, Shailesh (2003) Genetic defenses against noncholesterol sterols. Curr Opin Lipidol 14:341-5

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