What makes up the choroid plexus

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Somerford, A. A case of papilloma of the choroid plexus. However, even though neither the stroma nor the blood vessels induce choroid plexus formation, signaling from the stroma to the epithelial cells after stromal formation has been observed.

This was seen recently when Shh was deleted from the choroid plexus epithelial cells, which lead to a decrease in Shh-signaling in the Shh responsive cells choroid plexus progenitor cells and pericytes , which in turn resulted in a much smaller choroid plexus deficient in both vasculature and CPE cells Huang et al. Interestingly, this also leads us to one of the very few described regional differences between the choroid plexuses; Shh is not expressed in the forebrain choroid plexuses, suggesting that other molecules might be responsible for this regulation in the forebrain.

Conversely, it appears that Otx2, which is expressed in and has an effect on the initial development of all the choroid plexuses, may have alternative functions in the different choroid plexuses after their specification and initial development, as deletion at E15 only affected survival in the hindbrain choroid plexus Johansson et al. Further comparisons between the different choroid plexuses are currently under investigation. These criteria are of course all met in the adult choroid plexus via the presence of the blood-CSF barrier, the presence of the water channel AQP1 and the creation of ion gradients between blood and CSF via a multitude of ion transporters and exchangers see e.

Aquaporin-1, the only confirmed and consistently identified water channel in the choroid plexus, is present in the choroid plexus epithelial cells as soon as they start to differentiate Johansson et al. The gradient, however, that drives the water transport, does not appear to be regulated in the same manner as in the adult Johansson et al. For example, two of the main components in creating the ion gradients in the adult NaK-ATPase alpha subunit and carbonic anhydrase II are not present in the early developing choroid plexus Johansson et al.

Instead it has been suggested that the there is a colloid-osmotic gradient, created by the high protein concentration in CSF during development, that drives the water from blood or more accurately from interstitial fluid into CSF see Johansson et al.

Experimental evidence for this suggestion was recently described, where the total protein concentration in CSF was artificially increased via systemic protein injections in early development P9 Monodelphis Domestica , resulting in a transient doubling of the size of the lateral ventricles Liddelow et al. In both development and in the adult little is known about the transcriptional regulation of CSF secretion.

One transcription factor that appears to have a role in regulating CSF secretion is E2F5, which is expressed in the developing choroid plexus from E Its deletion homozygous full knock-out mice resulted in post-natal non-obstructive hydrocephalus Lindeman et al. However, as E2F5 protein levels appear to decrease in the choroid plexus as they mature and its localization is shifted from nuclear to cytoplasmic , it was suggested that E2F5 plays a role in the maturation process of CPE cells Lindeman et al.

It was also found that E2F5 is one of the target genes of choroid plexus specific micro-RNA mir, which is expressed through-out choroid plexus development Redshaw et al.

The continuous CSF production originating mostly from the choroid plexuses creates a pressure inside the cerebral ventricles. The requirement of this pressure for normal brain development was shown by a study in chick embryos Stage18 , where the intraventricular pressure was removed via insertion of hollow tubes into the ventricular system Desmond and Jacobson, After 24 h the nervous tissue had folded into the ventricles.

However, the choroid plexuses not only regulate the level of CSF production but also modify its composition. CSF composition can be regulated in two main ways; either via changes in the transfer of molecules from blood into CSF across the epithelium receptor or carrier mediated transfer as well as exclusion of molecules via efflux pumps or via changes in the secretion of molecules produced by the choroid plexuses themselves Figure 2.

In the developing choroid plexuses both of these mechanisms are in play. The subset of epithelial cells that transport proteins from blood into CSF are not only present in development but their proportion is larger and they appear to be more specialized as they selectively transport certain plasma proteins and not others across the barrier, a mechanism that appears to not be present in the adult for example see Johansson et al.

In regards to other proteins capable of modifying CSF composition in the adult efflux pumps, amino acid transporters, solute transporters , the majority are already present in the developing e.

In addition, recent choroid plexus transcriptome analyses have shown that the developing choroid plexuses also express a large amount of signaling type of molecules that can be secreted into the ventricles and affect the behavior of the neural stem cells lining the ventricles e. That CSF can modulate brain development has been shown in in vitro experiments.

Here it was shown that isolated cortical cells can be maintained on embryonic CSF alone Miyan et al. Neuroepithelial explants from chick were shown to survive and proliferate just as well in CSF serum free media as in serum supplemented media Gato et al. This is consistent with the age-dependent changes in CSF composition previously observed using both proteomics Zappaterra et al. The proteome study compared embryonic mouse CSF from three different ages and reported proteins in E Only proteins were common to all three ages, suggesting a highly dynamic regulation of CSF composition Zappaterra et al.

In studies investigating particular molecules, the levels of different plasma derived proteins was found to vary between different embryonic stages and although the individual proteins were following the same pattern increase, peak, and decrease the peak was reached at different ages Dziegielewska et al.

Igf2 was found in CSF from embryonic rat at all ages investigated but showed a significant increase late in embryogenesis and a decrease again perinatally Lehtinen et al. However, in a study measuring Shh levels, the concentration of this particular molecule did not change in mouse CSF between E Together these studies show a highly regulated control of CSF composition during development and during the period of neurogenesis.

In support of the regulation of CSF content having a physiological function, direct manipulation of CSF composition has been shown to alter the behavior of the stem cells in direct contact with the CSF. Here, both loss and gain of function experiments have been performed in vivo using either neutralizing antibodies or recombinant proteins injected into the embryonic ventricles.

For example, the removal of Fgf2 from chick CSF caused a loss of proliferation and increased neural differentiation Martin et al.

Similar experiments with another type of growth factor Igf1, in embryonic mice and rats, showed an increase in proliferation after intraventricular injections of recombinant proteins and a decrease after IGF-neutralizing antibodies were injected Mairet-Coello et al. Thus, the link between CSF composition and alteration in neural stem cell behavior has been experimentally shown but the link between choroid plexus development and brain development remains less clear.

The choroid plexuses appear whilst neurogenesis is occurring through-out the nervous system. This gives the potential for the choroid plexuses via their modulation of CSF to alter the behavior of the neural stem cells along the neuroaxis Figure 1 , Box 1.

As described above, the capability of the CSF to alter both proliferation and survival in different brains regions in vitro has long been known, likely due to the signaling molecules present in CSF. However, to what extent these molecules are regulated or even secreted by the choroid plexuses has not been sufficiently investigated perhaps in part due to the technical difficulties such an approach poses. With the advancement of region and time specific deletion techniques new strategies to isolate choroid plexuses involvement in neurogenesis are available.

Along these lines, some recent work has demonstrated, via choroid plexus specific deletions, that molecules expressed in the choroid plexus have the capability to influence brain development at other sites. Recently, in work done by the author and colleagues, it has also been shown that when the transcription factor Otx2 was deleted from the hindbrain choroid plexus using the Gd7-Cre only very sparse recombination in other regions it not only significantly altered the size of the choroid plexus but also the relative expression of many secreted signaling molecules Johansson et al.

To our surprise, this deletion led to a region-specific increase in proliferation in the far distant cerebral cortex but not in the spinal cord or in the lateral ganglionic eminence , which in turn led to site-specific alterations in the cortical neuronal layers at P7. The increase in proliferation was caused by an increase in Wnt-signaling, mediated by, at least in part, altered hindbrain choroid plexus expression levels and the ensuing increased CSF protein levels of the Wnt-signaling modulators Wnt4 and Tgm2.

This work revealed for the first time, the choroid plexus as a potential modulator of Wnt-signaling in the developing brain. It also highlighted that the hindbrain choroid plexus, being the first to appear, can alter the behavior of progenitor cells at the opposite end of the ventricular system prior to the differentiation of the other choroid plexuses.

This period is also notable as the ventricular system is still an enclosed cavity, not connected with the fluid in the subarachnoid space and does not yet have any directional flow, making it more possible for molecules secreted from the fourth ventricular choroid plexus to reach the forebrain and influence the behavior of the neural stem cells Figure 4.

In support of this, in the above study we also found that the increase in proliferation and Wnt-signaling was no longer present at E16, when the influence of the hindbrain choroid plexus would be much reduced due to the now much larger unaffected lateral ventricular choroid plexuses in closer proximity to the cortical neural stem cells Johansson et al.

Figure 4. Simplified schematic drawing of how choroid plexus mediated changes in CSF composition differentially alters the behavior of the neural stem cells along the neuroaxis via differences in their ability to respond here exemplified by the presence and density of receptors. We suggest that select tissues are prepared for certain signaling molecules, by the expression of not only receptors but also by the expression of modulators and inhibitors of the different signaling pathways.

Thus, neurogenesis can be seen as a reciprocal process between the choroid plexus and the neural stem cells mediated via the CSF Figure 4. In conclusion, there is substantial evidence that there is indeed a role played by the choroid plexus-CSF-signaling axis in the modulation of developmental neurogenesis.

However, much more remains to be discovered. The specific mechanisms by which the choroid plexuses modulate brain development both in terms of the choroid plexuses as whole organs as well as specific aspects of their functions e. Further detailed studies of choroid plexus impact on different brain regions and developmental time-points would increase our understanding of the whole process of brain development.

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Citation, DOI and article data. Nguyen, M. Choroid plexus. The ependymal cells of the choroid plexus produce up to milliliters ml a day of CSF in the average adult.

The composition of the CSF itself is similar to blood plasma with an altered concentration of electrolytes, such as a higher amount of sodium, magnesium, and chloride with lower amounts of potassium and calcium. It may contain small numbers of white blood cells.

This fluid is filtered by the fenestrated capillaries that help to make up the choroid plexus. The composition of CSF is further regulated by the microvilli, which reside on the surface of cells that make up the choroid plexus and act to absorb CSF when necessary. The blood-CSF barrier is formed by the epithelial cells of the choroid plexus, which are linked together with tight junctions and envelop a network of fenestrated capillaries.

The epithelial cells face the ventricles of the brain. The other portion of the blood-CSF barrier is the arachnoid membrane, one of the meninges that surround the brain. The blood-CSF barrier prevents harmful substances from entering the brain while also allowing harmful waste to exit back into the bloodstream. Water is allowed to pass the blood-CSF barrier and is used to manufacture cerebrospinal fluid. Impairment of the blood-CSF barrier can allow the entrance of harmful microbes into the CSF, leading to dangerous inflammation in the meninges surrounding the brain and spinal cord.

Several different types of germs can cause meningitis, including viruses, bacteria, fungi, and parasites. Non-infectious meningitis can be related to conditions such as certain types of cancers or lupus. Hydrocephalus is a condition where there is too much CSF in the brain due to a blockage such as a growth or tumor , preventing proper flow of CSF; the overproduction of CSF; or a problem with the way CSF is normally absorbed. This extra fluid in the brain can cause symptoms such as headache, convulsions, vision disturbances, and mental difficulties, and long-term problems can result if it is left untreated.

Hydrocephalus is normally treated using a shunt, which diverts the extra fluid away from the brain to a location where it can be reabsorbed. Cerebrospinal fluid leaks are the result of a tear or hole in the dura surrounding the brain, which allows CSF to leave the subarachnoid space. This can be caused by a traumatic injury usually to the head or face , rarely as a complication of sinus surgery, or as a complication of lumbar puncture or epidural anesthesia.

It can also be congenital. Spontaneous CSF leaks are rare. They may be due to an underlying condition or lack an identifiable or obvious cause.

A CSF leak can cause clear watery fluid to run from your nose or ears , a headache that may get worse or improve when you change positions, or ringing in your ears tinnitus. It can also lead to meningitis, since the hole in the dura creates a pathway for microbes to enter the subarachnoid space.