Modification of gene expression and soluble factor secretion in the lateral ventricle choroid plexus: Analysis of the impacts on the neocortical development.

The choroid plexus (ChP) is the center of soluble factor secretion into the cerebrospinal fluid in the central nervous system. It is known that various signaling factors secreted from the ChP are involved in the regulation of brain development and homeostasis. Intriguingly, the size of the ChP was prominently expanded in the brains of primates, including humans, suggesting that the expansion of the ChP contributed to mammalian brain evolution, leading to the acquisition of higher intelligence and cognitive functions. To address this hypothesis, we established transgenic (Tg) systems using regulatory elements that direct expression of candidate genes in the ChP. Overexpression of sonic hedgehog (Shh) in the developing ChP led to the expansion of the ChP with greater arborization. Shh produced in the ChP caused an increase in neural stem cells (NSCs) in the neocortical region, leading to the expansion of ventricles, ventricular zone and neocortical surface area, and neocortical surface folding. These findings suggest that the activation of Shh signaling via its enhanced secretion from the developing ChP contributed to the evolution of the neocortex. Furthermore, we found that Shh produced in the ChP enhanced NSC proliferation in the postnatal Tg brain, demonstrating that our Tg system can be used to estimate the effects of candidate factors secreted from the ChP on various aspects of brain morphogenesis and functions.

Sonic hedgehog expands neural stem cells in the neocortical region leading to an expanded and wrinkled neocortical surface.

An expanded and folded neocortex is characteristic of higher mammals, including humans and other primates. The neocortical surface area was dramatically enlarged during the course of mammalian brain evolution from lissencephalic to gyrencephalic mammals, and this bestowed higher cognitive functions especially to primates, including humans. In this study, we generated transgenic (Tg) mice in which the expression of Sonic hedgehog (Shh) could be controlled in neural stem cells (NSCs) and neural progenitors by using the Tet-on system. Shh overexpression during embryogenesis promoted the symmetric proliferative division of NSCs in the neocortical region, leading to the expansion of lateral ventricles and tangential extension of the ventricular zone. Moreover, Shh-overexpressing Tg mice showed dramatic expansion of the neocortical surface area and exhibited a wrinkled brain when overexpression was commenced at early stages of neural development. These results indicate that Shh is able to increase the neocortical NSCs and contribute to expansion of the neocortex.