Partial rescue of neonatal lethality of Dhcr7 null mice by a nestin promoter-driven DHCR7 transgene expression. Brain Res Dev Brain Res 2005 Apr 21;156(1):46-60
Date
05/03/2005Pubmed ID
15862627DOI
10.1016/j.devbrainres.2005.01.012Scopus ID
2-s2.0-18044377392 (requires institutional sign-in at Scopus site) 15 CitationsAbstract
In humans, genetic disorders affecting post-squalene cholesterol biosynthesis result in a variety of dysmorphology syndromes. One key feature of all of these is the presence of mental retardation and another is the lack of a robust genotype-phenotype correlation. Knockout mice defective in the 3beta hydroxysterol Delta7 reductase (Dhcr7), a model for the most common of such disorders in humans, the Smith-Lemli-Opitz syndrome, all die within 24 h of birth. The cause of this postnatal mortality in these mice has not been fully established. In the present study, we tested the hypothesis that CNS dysfunction was a major cause of this lethality and investigated whether transgenic expression of normal human DHCR7 in neuronal tissues could rescue this neonatal lethality. Transgenic mice, expressing DHCR7 driven by murine nestin promoter, were bred onto Dhcr7 knock-out (Dhcr7(-1-)) background and resulted in a partial rescue of neonatal lethality in 11 of 91 (12%) of transgene-positive Dhcr7(-1-) pups. Despite biochemical analyses that showed continued profound cholesterol deficiency in brain, rescued animals survived between 3 and 17 days. Thus, one important conclusion to be drawn is that defects in CNS in Dhcr7 knockout mice may contribute to the early lethality. Another conclusion is that even small and subtle changes in the brain sterol metabolism were sufficient to enable rescue. These data also provide important clues as to the cause of the variable expressivity seen in SLOS.
Author List
Yu H, Wessels A, Tint GS, Patel SBAuthor
Hongwei Yu MD Professor in the Anesthesiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Age FactorsAnimals
Animals, Newborn
Blotting, Northern
Brain
Gas Chromatography-Mass Spectrometry
Gene Targeting
Humans
Immunohistochemistry
Intermediate Filament Proteins
Kidney
Liver
Lung
Mice
Mice, Transgenic
Microscopy, Electron, Transmission
Molecular Biology
Mutation
Nerve Tissue Proteins
Nestin
Oxidoreductases Acting on CH-CH Group Donors
Promoter Regions, Genetic
Spinal Cord
Sterols
Transgenes
