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

Abstract

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.

Keywords: Brain morphogenesis; Choroid plexus; Neocortical development; Neural stem cell; Neurogenesis; Sonic hedgehog.