title: Altered cholesterol biosynthesis causes precocious neurogenesis in the developing mouse forebrain.
abstract: We previously reported a mutation in the cholesterol biosynthesis gene, hydroxysteroid (17-beta) dehydrogenase 7 (Hsd17b7(rudolph)), that results in striking embryonic forebrain dysgenesis. Here we describe abnormal patterns of neuroprogenitor proliferation in the mutant forebrain, namely, a decrease in mitotic cells within the ventricular zone (VZ) and an increase through the remainder of the cortex by E11.5. Further evidence suggests mutant cells undergo abnormal interkinetic nuclear migration (IKNM). Furthermore, intermediate progenitors are increased at the expense of apical progenitors by E12.5, and post-mitotic neurons are expanded by E14.5. In vitro primary neuron culture further supports our model of accelerated cortical differentiation in the mutant. Combined administration of a statin and dietary cholesterol in utero achieved partial reversal of multiple developmental abnormalities in the Hsd17b7(rudolph) embryo, including the forebrain. These results suggest that abnormally increased levels of specific cholesterol precursors in the Hsd17b7(rudolph) embryo cause cortical dysgenesis by altering patterns of neurogenesis.
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Driver
authors.affiliation: Kennedy Krieger Institute, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Kratz
authors.affiliation: Department of Genetics & Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Kelley
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Electronic address: rolf.stottmann@cchmc.org.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Stottmann
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002784:Cholesterol / Q000096:biosynthesis*; D004622:Embryo, Mammalian / Q000378:metabolism; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D016548:Prosencephalon / Q000254:growth & development / Q000378:metabolism*
chemical_list: D009419:Nerve Tissue Proteins; D002784:Cholesterol
keywords: Cell fate; Cholesterol biosynthesis; Cortical neurogenesis; Development; Forebrain; Hsd17b7; Mouse; Neural progenitors; Neurogenesis; Statin