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 (Hsd17b7rudolph), 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 Hsd17b7rudolph embryo, including the forebrain. These results suggest that abnormally increased levels of specific cholesterol precursors in the Hsd17b7rudolph embryo cause cortical dysgenesis by altering patterns of neurogenesis.

Lipid Mediated Regulation of Adult Stem Cell Behavior

“…Mechanistically, Spot14 decreases FASN activity by dimerizing with Mig12, an activator of ACC, thereby inhibiting its function and causing a decrease of ACCmediated malonyl-CoA production, leading in a reduction in FA synthesis (Knobloch et al, 2013). Of note, it was suggested that cholesterol biosynthesis, which occurs through an independent pathway, is also required for NSPC self-renewal and maintenance in the developing mouse forebrain, as NSPCs with mutations in enzymes involved in this pathway exhibit premature differentiation into neurons, causing exhaustion of the stem cell pool (Driver et al, 2016). Importantly, as in the case of NSPCs, increased lipid anabolism in Drosophila GSCs through the activation of SREBP also resulted in stem cell loss (Sênos Demarco et al, 2019), suggesting that a conserved mechanism may be at play across stem cell populations.…”

Mutations in the zebrafishhmgcs1gene reveal a novel function for isoprenoids during red blood cell development

“…Given the role of cholesterol in the RBC membrane, it is plausible that cholesterol regulates cell survival. However, the function of the CSP might not be limited to cell death or stress mechanisms because previously published work has indicated a regulatory function for cholesterol and its derivatives at the level of cellular differentiation [53][54][55][56][57][58][59][60] . Future work that analyzes both primitive and definitive hematopoiesis at unique stages of differentiation in different model systems is likely to identify the exact cellular mechanisms underlying the phenotypic alteration we describe.…”

The Implications for Cells of the Lipid Switches Driven by Protein–Membrane Interactions and the Development of Membrane Lipid Therapy

“…Interestingly, decreased Chol biosynthesis has little effect on NSPC proliferation when compared to its effect on newborn neurons, which undergo massive death by apoptosis when Chol is limited. Similarly, the radial glial network that supports the migration of newborn neurons also seems to be affected by changes in Chol [139,140]. Consequently, reduced Chol levels at cell membranes seems to compromise brain neurogenesis and NSPC migration.…”

“…Consequently, reduced Chol levels at cell membranes seems to compromise brain neurogenesis and NSPC migration. Weaker Chol biosynthesis affects the mitotic behavior of NSPCs and it induces premature differentiation into neurons, which could explain why newborn neurons undergo apoptosis in these conditions [140]. Interestingly, these defects can at least be partially prevented by feeding pregnant animals Chol supplemented diets [140].…”