Altered cholesterol biosynthesis causes precocious neurogenesis in the developing mouse forebrain

NEUROBIOLOGY OF DISEASE

卷:91

Article

Driver, Ashley M.¹  Kratz, Lisa E.²  Kelley, Richard I.³  Stottmann, Rolf W.^1,4 

[1] Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA

[2] Johns Hopkins Univ, Kennedy Krieger Inst, Baltimore, MD 21205 USA

[3] Boston Childrens Hosp, Dept Genet & Genom, Boston, MA 02115 USA

[4] Cincinnati Childrens Hosp Med Ctr, Div Dev Biol, Cincinnati, OH 45229 USA

关键词: Cortical neurogenesis;    Cholesterol biosynthesis;    Cell fate;    Neural progenitors;    Forebrain;    Neurogenesis;    Mouse;    Hsd17b7;    Statin;    Development;   

DOI  :  10.1016/j.nbd.2016.02.017

来源: Elsevier

【 摘 要 】

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. (C) 2016 Elsevier Inc. All tights reserved.

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