Fate of Neural Cells in Developing Mammalian Forebrain Could Hinge on Cholesterol Biosynthesis Enzyme

Published Online February 24, 2016
Neurobiology of Disease

Research into the developing forebrain of mice shows for the first time that loss of proper cholesterol biosynthetic enzyme function can alter the very fate of the neural cell.

The study follows up on previous research in which the team reported that a mutation in hydroxysteroid (17-beta) dehydrogen-ase 7 (Hsd17b7) resulted in “striking” embryonic forebrain congenital malformations.

This study adds several new observations. Evidence suggests mutant cells undergo abnormal interkinetic nuclear migration. Intermediate progenitors increase at the expense of apical progenitors. Also, an in vitro primary neuron culture supports the team’s model of accelerated cortical differentiation in the mutant.

The findings show how much neural cells rely on proper enzyme function to keep brain development on course.

“Specifically, neural stem cells in the brain of mutant embryos are differentiating into mature neurons at a rate significantly faster than in normal developing brains,” says senior author Rolf Stottmann, PhD.

As a result, the embryos were unable to maintain critical stem cell populations and exhibited dramatic reductions in brain cell formation.

The team, led by first author Ashley Driver, PhD, also reported early steps toward a potential treatment. In utero administration of statins and dietary cholesterol produced partial rescue of brain development.

“This is a nice demonstration,” Stottmann says, “of the power of forward genetics in the mouse to identify new genes and go on to uncover fundamental mechanisms of mammalian development and disease."

Next, the team plans to study how enzyme synthesis malfunctions might affect other congenital malformations.