Defective cell cycle control underlies abnormal cortical development in the hydrocephalic Texas rat.

There is a significant body of evidence to suggest a physiological role for the CSF in both the developing and adult brain. Our recent studies suggest a critical role for this fluid in the developing brain of the hydrocephalic Texas (H-Tx) rat. A key feature of the foetal-onset hydrocephalus in this rat is obstruction in the flow and/or absorption of fluid that is associated with abnormal development of the cerebral cortex resulting in a reduction in the number of neuronal precursors generated. Cells from the affected cerebral cortex do proliferate in vitro and show dose-dependent responses to growth factor stimulation, suggesting that germinal cells are under inhibitory influences in vivo. We tested the hypothesis that the CSF of the affected brains was responsible for the abnormal development. Cells analysed at the time of extraction from affected brains showed an accumulation of cells in the S-phase of the cell cycle, which was reflected in a concentration of cells containing high levels of DNA in the germinal matrix of histological sections of affected brains. CSF from the lateral ventricle of affected foetal brains not only inhibited in vitro proliferation of normal neuronal progenitors, but it also resulted in an accumulation of cells in the S-phase of the cell cycle mimicking the situation in vivo. Fluid from normal foetal brains did not have this effect. From the work detailed here on the mechanistic basis of the deficient cortical development in the foetal hydrocephalic rat brain, we conclude that the content of the CSF is critical in maintaining germinal matrix function and output and, therefore, that the CSF has a vital role in brain development.

Deficient cortical development in the hydrocephalic Texas (H-Tx) rat: a role for CSF.

The objectives of this study were to demonstrate the presence and nature of abnormal cortical development in a rat model of hydrocephalus, the hydrocephalic Texas (H-Tx) rat, and to test the hypothesis that the obstruction of CSF flow in affected animals can be linked to this effect. CSF is secreted continuously by the choroid plexus, located in the lateral, third and fourth ventricles. The fluid flows through the ventricular system, passing over all regions of germinal activity. In the H-Tx rat, obstruction and eventual blockage of CSF flow occurs in the cerebral aqueduct, between the third and fourth ventricles, at embryonic day 18. Prior to obstruction, neurogenesis and migration occur as in normal rats. Here we show that, following obstruction of fluid flow, neurogenesis from the germinal epithelium becomes abnormal. Cell proliferation decreases and proliferating cells are not retained in the germinal layer, as they appear to be in the normal brain. Cell migration is apparently unaffected, although a decrease in the number of migrating cells does occur after CSF obstruction. These data from our study indicate that a rapid primary effect of CSF obstruction, prior to any mechanical effects of fluid accumulation, is to alter the activity of cells in the germinal epithelium of the developing cortex. Further evidence for this is gained from in vitro studies. Once removed from their in vivo environment, cortical cells from the H-Tx rat have the ability to proliferate as normal. CSF extracted from the enlarged ventricles of affected brains is able to inhibit the proliferation of normal cells. Thus, we hypothesize that CSF has a potential role in the developmental process. The damming up and accumulation of CSF, whatever the cause, may result in abnormal cortical development through accumulation of CSF factors that are, or become, inhibitory to normal neuronal proliferation.