Brain, Vol. 126, No. 3, 623-631,
March 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg058
Defective cell cycle control underlies abnormal cortical development in the hydrocephalic Texas rat
1 Foetal Management Unit, St Mary’s Hospital, 2 Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology, Manchester and 3 Department of Biological Sciences, University of Lancaster, Lancaster, UK *These authors contributed equally to this study.
Correspondence to: Dr Jaleel Miyan, Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology, PO Box 88, Sackville Street, Manchester M60 1QD, UK E-mail: j.miyan{at}umist.ac.uk
Received July 10, 2002. Revised September 16, 2002. Second revision October 8, 2002. Accepted October 16, 2002..
 |
Summary |
|---|
 Top Summary IntroductionMethodsResultsDiscussionReferences |
|---|
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.
Keywords: cerebrospinal fluid; hydrocephalus; cerebral cortex; development; cell cycle
Abbreviations: bFGF= basic fibroblast growth factor; H-HTx = affected H-Tx rats; H-Tx = hydrocephalic Texas rats; GM = germinal matrix; LSD = least significant differences; N-HTx = unaffected H-Tx rats
|
Introduction |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
In the adult human, CSF is secreted by the choroid plexuses within the brain ventricular system at a rate of 0.3 ml/min. This produces four times the volume that is held in the fluid spaces of the brain per day. This fluid moves by bulk flow from its source, through the ventricles and out over the surface of the brain to sites of absorption, mainly thought to be the arachnoid villi that empty into the sagittal venous sinus and the facial lymphatics. Obstruction of CSF flow can occur for many different reasons and leads to hydrocephalus, a condition affecting 2–3 per thousand live human births (Matsumoto and Tamaki, 1991
; Rekate, 1997; McAllister and Chovan, 1998). In the past, the obvious effects of this condition, if left untreated, were thought to be related to brain damage caused by raised intracranial pressure due to accumulation of CSF in the brain. As a result, clinical and scientific research has also been largely restricted to thinking that fluid accumulation and raised pressure are the sole factors responsible for the effects seen (Frim et al., 1998). The vast majority of studies have concentrated on the post-natal effects of raised intracranial pressure and the efficacy of CSF diversion, i.e. shunt treatment or third ventriculostomy, at different times after the onset of hydrocephalus. However, another feature often overlooked is that foetal-onset hydrocephalus results in a wide range of neurological deficiencies in the affected children, which are not prevented or recovered by shunt treatment (McAllister and Chovan, 1998). Our data now support the view that these are due to deficient cortical development due to CSF obstruction during the foetal stages (Mashayekhi et al., 2002).
Rapid advances in the understanding of brain development have provided a framework for our analysis of cortical development in foetuses affected by CSF obstruction in the hydrocephalic Texas (H-Tx) rat, a widely recognized model for this condition (Jones and Bucknall, 1988; Harris et al., 1992, 1996; Jones et al., 1993, 1995, 2001; Oi et al., 1996; Hawkins et al., 1997; Oi, 1998; Mashayekhi et al., 2002). These rats arose as a spontaneous mutation in a normal colony and have been maintained through brother–sister mating (Kohn et al., 1984; Oi et al., 1996; Jones et al., 2000). Mothers produce litters where 
40% of the pups have an obstruction of the cerebral aqueduct between the third and fourth ventricles that leads to hydrocephalus (Jones and Bucknall, 1988; Jones, 1997; Oi, 1998; Pourghasem et al., 2001). In affected pups, the obstruction occurs on day E18 and produces a block in the flow of CSF within the ventricular system and around the brain. Detailed analysis of the development of the cortex in affected hydrocephalus foetuses has shown that there is a reduction in the width of the cortex and a lack of stratified layers of neurons generated after the obstruction. This is due to a reduction in the numbers of neurons leaving the germinal matrix (GM) because of reduced neurogenesis at this site (Mashayekhi et al., 2002).
Our previous paper pointed towards a role for CSF in this deficient neuronal output. In agreement with our results, there is now a body of evidence that points towards a critical role of the CSF in brain development and physiology. CSF contains growth factors and cytokines secreted from the choroid plexus as well as the subcommissural organ (Schoniger et al., 2002), which are known modulators of neurogenesis, differentiation and the brain extracellular microenvironment and which show changes associated with neurological disorders and disorders of development (Kasaian and Neet, 1989; Jones et al., 1991; Kitazawa and Tada, 1994; Suzaki et al., 1997; Arnold et al., 1999; Johanson et al., 1999, 2001; Nicholson, 1999; Moinuddin and Tada, 2000; Proescholdt et al., 2000; Xia et al., 2000; Johanson and Jones, 2001). Constituents of CSF change during development and in response to physiological challenges and are capable of contacting cells in the cortical parenchyma (Kasaian and Neet, 1989; Mogi et al., 1996; Suzaki et al., 1997; Heinze et al., 1998; Korhonen et al., 1998; Arnold et al., 1999; Van Setten et al., 1999; Biou et al., 2000; Grouzmann et al., 2000; Proescholdt et al., 2000). Manipulation of CSF volume (in chick embryos) or growth factor content (in adult rodents) can result in a failure of normal cortical development and/or hydrocephalus (Johanson et al., 1999; Moinuddin and Tada, 2000). In this paper, we have characterized the effects of CSF on GM cell function and started to define the mechanism for CSF alteration of GM cell function.
|
Methods |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
Maintenance of H-Tx colony
All experiments were sanctioned by the Home Office Animal Procedures Inspectorate. Both Wistar and H-Tx rat colonies were maintained on 12:12 h light dark cycle beginning at 8.00 am. They were kept at a constant temperature in large rat boxes with unrestricted access to food and water. The H-Tx colony was maintained through brother–sister mating between unaffected males and females, whilst the Wistar colony was maintained through random pair mating. Timed mating was carried out by placing a male and female together in a box and checking for the presence of a vaginal plug every hour. The presence of a plug was taken to indicate successful mating and the time taken as gestational day zero.
Analysis points
Foetuses from timed pregnancies of H-Tx rats were harvested after sacrifice of the mother, by overdose of anaesthetic (sodium pentobarbitone), at gestation days 14–16 (pre-obstruction), 17–18 (time of obstruction) and 19–21 (post-obstruction) in order to investigate prenatal cortical development. Pups on the day of birth or the day after birth were also investigated. Foetuses were decapitated and brains were removed and processed as described below. Post-natal pups were killed by overdose of anaesthetic (sodium pentobarbitone) and brains removed and processed as described below. Opacity of the head to transillumination and enlarged ventricles were the main criteria used to identify affected H-Tx foetuses along with histological evidence for aqueduct obstruction (Mashayekhi et al., 2002). Affected foetal heads appeared brighter under transillumination due to the greater fluid volumes and decreased density of brain tissue.
Preparation of tissue samples
Brains were fixed in ice cold 4% paraformaldehyde in phosphate buffered saline (PBS) at pH 7.3. Fixation was carried out for a minimum of 2 h and usually overnight. Fixed brains were then washed and placed in 20% sucrose solution for 12–24 h before embedding in OCT compound (Bright Instruments, Huntingdon, Cambridge, UK) and freezing in isopentane cooled with dry ice. Coronal sections were cut at 15 µm on a Slee cryostat and collected onto subbed slides for staining and analysis. Comparable sections were taken at the mid-line to contain the anatomical landmarks of the hypothalamus taken immediately after the optic chiasm (Mashayekhi et al, 2002). Sections were stained with 5 µM bis-benzimide (Hoechst 33342, Sigma-Aldrich, Poole, UK), mounted in glycerol–gelatin and imaged by fluorescence microscopy. Digital images were acquired with fixed exposure time and the staining was analysed using Metaview software (Universal Imaging Corp. Ltd, Downingtown, PA, USA). Quantitative intensity data were generated by drawing a perpendicular line from the ventricular ependymal margin to the pial meningeal margin. The thickness of the line was adjusted to enclose 10 cell diameters. The software then produced a histogram of average intensity along the length of the line. Thus, the data are a measure of mean intensity through the cortex.
Proliferation assay
Cortical hemispheres from the brains of embryonic day 19 Wistar (normal, control) or day 20 H-Tx rat foetuses [divided into two groups: unaffected H-Tx (N-HTx) and affected H-Tx (H-HTx)] were used to prepare cultures. Due to a 12–24 h difference in gestational times between the H-Tx and Wistar strains, we found that Wistars taken a day before H-Tx were matched on foetal weight and histological parameters (cortical thickness and number of cortical layers). For each group, 4–6 cortical hemispheres were cleared of meninges and incubated in Trypsin–EDTA solution (0.25%) at 37°C for 20 min. The solution was replaced with neurobasal medium (Invitrogen, Paisley, UK) and the cells dissociated by repetitive pipetting through tips of decreasing bore size. The suspension was centrifuged at 1700 r.p.m. for 5 min and the media replaced with fresh media. Further pipetting was performed to break up clusters of cells before a sample was taken for viability staining with trypan blue (0.4%) and cell counting. The dissociated cells were plated in poly-D-lysine (0.05 mg/ml) coated 96-well plates at a density of 1 x 104 cells/ml in neurobasal medium, which preferentially supports progenitor and neuronal cell types (not glial cells), containing B27 supplement (Invitrogen), 2 mM glutamine and penicillin–streptomycin (0.1 mg/ml, Sigma-Aldrich, Poole, UK). Additions of basic fibroblast growth factor (bFGF) were made at different concentration (as indicated in the figure legends) and the cultures were maintained at 37°C in a 5% CO2 atmosphere.
Proliferation of cells was determined using the luminescence-based Lumitech Vialight high sensitivity cell proliferation and cytotoxicity kit (LumiTech Ltd, Nottingham, UK) as per manufacturer’s instructions. We performed an analysis of the luminescence reading against known viable cell number for cells from the affected and unaffected foetuses. This assay can detect as few as 100 viable cells in the culture and there is no difference between the observed luminescence against cell number for any of the cell types used. The assay is thus highly sensitive in comparison with other methods for determining the number of cells within a culture and measures cells that have actually completed division; unlike alternative methods, which measure incorporation of nucleotides into DNA. Measurements were made on a Multilabel Counter (Wallac Victor2 1420, Perkin-Elmer, Shelton, Connecticut, USA). Results are expressed as mean luminescence ±SEM (n = 3) of at least three experiments involving at least three litters, each performed in triplicate.
In experiments to determine the effect of CSF on cortical cell cultures, CSF was removed by tapping the cisterna magna of unaffected H-Tx and Wistar foetuses, and the lateral ventricle of affected H-Tx. This CSF was added to the cultures as indicated in the legend to Fig. 5. The cisterna magna is an excellent site to collect uncontaminated CSF since the fluid space is large and access is through a thin membrane once the overlying musculature is dissected. Occasional contamination with blood was caused by severing a blood vessel within the cisternal cavity and these samples were discarded. All samples were collected into sterile Eppendorf tubes and routinely centrifuged twice at 14 000 r.p.m. to remove any cells or debris from the fluid, which was decanted into another sterile tube. The lateral ventricle of affected H-Tx foetuses also provides uncontaminated CSF, since it is dilated with accumulated fluid and presents a large fluid space free of blood vessels. Occasional contamination with blood does occur due to needle puncture through a cranial blood vessel. These samples were discarded and clear samples centrifuged as described above. Samples were frozen on dry ice and stored at –80°C until used. Control experiments with normal CSF suggest that the collection technique was contamination free (see Results and Discussion). We were able to collect between 5 and 50 µl of CSF from normal foetuses and up to 100 µl from the lateral ventricle of affected foetuses using these methods.
|
Cell cycle analysis
Cells were plated at a density of 1 x 104 cells/ml in poly-D-lysine (0.05 mg/ml) coated 24-well plates. The cells were trypsinized and fixed with ice-cold 70% methanol at time 0 (immediately following isolation from foetal brains) and after 24, 48 and 96 h in culture. Cells were stained with propidium iodide (5 µg/ml) and analysed using a flow cytometer (Becton Dickinson Facscaliber, Oxford, UK). The proportion of cells in G0/G1, S and G2-M phases of the cell cycle were quantified and plotted using a Modfit package (Verity Software, Topsham, Maine, USA). Results are expressed as mean proportion ±SEM (n = 3) of three experiments involving at least three litters, each performed in triplicate.
Statistical analysis
Analysis was performed using one-way ANOVA (analysis of variance) for grouped sets of data with further analysis for significantly different pairs using the post hoc test for least significant differences (LSD). Significance data displayed on the figures or quoted in the text relate to the results from the LSD tests.
|
Results |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
In vitro proliferation of GM cells from foetal brains
One possibility for reduced neurogenesis in the affected H-Tx cortex is that the GM cells are unable to proliferate. In order to test this possibility, GM cells were isolated into in vitro cultures and their proliferative potential in the absence of growth factors was analysed. In common with cells from unaffected or control Wistar foetuses, GM cells from the cortex of affected H-Tx proliferated under our culture conditions (Fig. 1). In the absence of added growth factor and after a 24 h lag time for cell recovery, the GM cells from affected foetuses display enhanced proliferation over a 96 h period compared with their unaffected littermates or normal rat controls (P = 0.01, Fig. 1).
|
The above data were generated in cell cultures containing no added growth factors. It remained possible that the affected GM cells lacked an ability to respond to externally added factors. bFGF is commonly used to maintain neuronal precursors in culture. Addition of this growth factor to our in vitro cultures resulted in a dose-dependent rise in proliferation of cells from both normal and affected foetal cortices (Fig. 2). The responses of the two cell types are similar, with statistically significant (P < 0.05) proliferation above the ‘no addition’ controls being observed at 30 ng/ml in both cases, although the affected cells have a higher starting proliferation index. This higher proliferation rate reflects the effect of removing cells from the in vivo environment (Fig. 1 and see below). Once removed from this environment, however, the cells behave in a similar manner to cells removed from normal brains. Thus, the GM cells from the affected foetuses do not have an inherent proliferation defect or any down-regulation of their responsiveness to bFGF. This raises the possibility that these cells are under an inhibitory influence in their in vivo environment.
|
GM cells from the hydrocephalic cortex are arrested at the S-phase of the cell cycle
Flow cytometric analysis of the cells at the point of extraction demonstrates that there is a statistically significant (P < 0.05) increase in the percentage of cells in S-phase of the cell cycle in GM cells from affected foetal brains compared with those from unaffected littermates. This persists for up to 24 h after removal (P < 0.01) of the cells into culture (Fig. 3). At later time points, the affected and unaffected populations become equivalent in terms of their cell cycle distributions. There is also a qualitative but not significantly different effect on the percentage of cells in the G2-M phase of the cycle (Fig. 3C). The data again demonstrate that the in vivo environment of the cells maintains an inhibitory influence on the cells and that release from this environment exposes the fact that the cells are otherwise normal and begin to follow the normal pattern of cell cycle kinetics.
|
This increase in the number of cells with more than the diploid (2n) quantity of DNA can also be seen in histological sections. Coronal sections through the cortex were stained with the DNA binding agent Hoechst 33342 (Fig. 4A and B). Because the staining was of sections rather than isolated cells and because the section thickness was greater than a single cell, it was not possible to make quantitative measurements. However, it was certainly possible to identify areas of the affected HTx cortex with cells containing significantly greater DNA staining than that observed in unaffected cortices. No evidence of oedema is visible in these sections and staining was localized to nuclei when viewed at higher magnification. False colour analysis of such images shows that there is an increase in the average single cell intensities in the affected H-Tx GM (Fig. 4C and D). Thus, there is quantitatively more DNA per cell in these cells. Our previous bromodeoxy uridine (BrDu) staining data however shows that there is minimal proliferation in this population (Mashayekhi et al., 2002
). Together these results and the in vitro analyses (Fig. 3) point to the GM cells in the affected H-Tx rat being blocked in the S-phase of the cell cycle. This inhibition of cell cycle progression is relieved following their removal from the in vivo environment
|
Role of CSF in abnormal GM cell function
The fact that the GM cells from affected rats are able to proliferate and respond in vitro suggests that there is an external factor within the in vivo environment which is inhibiting their function. The obvious defect in affected rats is a lack of flow of CSF around the brain. One possibility is that factors within this fluid are critical to the normal function of GM stem cells and our earlier data showed that CSF can in fact inhibit proliferation in vitro. Cells from unaffected and affected foetuses were incubated in media alone, media plus 10% PBS or 10% CSF from either normal or affected foetal brains (Fig. 5A). Cells from both normal and affected brains show a significant reduction in proliferation (P < 0.001 in both cases) in the presence of CSF from affected H-Tx foetuses. In fact, in the presence of this CSF, no significant proliferation occurs over the 96 h period. CSF from unaffected foetuses had no effect at this concentration. Moreover, cells from normal foetal brains showed a dose-dependent decrease in proliferation when exposed to CSF from affected foetuses (Fig 5B) with significant inhibition being observed at 2.5% CSF in the culture (P < 0.01). The CSF was not inherently toxic to the cells as the cells remained viable within the cultures but did not proliferate, maintaining luminescent values at starting levels. Thus, the inhibition of proliferation of GM stem cells in vivo is probably due to the lack of CSF flow resulting in local alterations in the composition of the CSF.
If the lack of flow of CSF was responsible for the reduction of proliferation in the GM cells, then we hypothesized that the CSF from the affected H-Tx should block the cell cycle in vitro. This is indeed the case (Table 1), as addition of 5% CSF to cultures of GM cells from normal foetuses resulted in an approximate doubling of the proportion of cells in the S-phase of the cell cycle. This mimics the site of and extent of blockage seen in affected GM cells immediately after their removal from their in vivo environment.
|
|
Discussion |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
Development of the cerebral cortex in the foetal H-Tx rat proceeds as normal until day E18, when the CSF is obstructed between the third and fourth ventricles. Following this obstruction, there is abnormal development of the cortex in which insufficient neurons are generated to populate the upper layers of the cortex resulting in reduced cortical thickness and ventricles that remain enlarged (Mashayekhi et al., 2002
). The abnormal cortex is the result of modified development and not the result of damage due to fluid accumulation and/or raised intracranial pressure that occurs after birth. Our previous studies implicate changes in the activity of neuronal progenitors that are located in the GM in this modified development (Mashayekhi et al., 2002). Work presented here demonstrates that the GM cells in the affected H-Tx rat are not inherently defective. They have the ability to proliferate normally and to respond to external factors such as bFGF when removed from their in vivo environment into culture. However, these cells appear to be blocked in the S-phase of the cell cycle in their in vivo environment and this blockade is lifted once they are removed into culture medium containing no added growth factors. Release from the in vivo inhibition is reflected in an increased proliferation with the release from the S-phase block. The in vivo blockade can be mimicked in vitro by inclusion of CSF from affected H-Tx foetuses in culture with cells from either normal or affected animals.
All of the evidence above suggests that it is likely that it is the CSF that inhibits GM cell proliferation in vivo. This is probably a result of changes in the concentration of certain CSF components due to the obstruction in fluid flow. Alternatively, there may be a new factor in the CSF, released as a result of altered choroid plexus output which gives the dose-dependent inhibition observed in vitro. Preliminary analysis of protein components does show significant differences in the CSF of affected compared with normal foetuses and these are currently under investigation in our laboratory.
The CSF flow pathway brings the fluid into close association with the subventricular germinal zones, where neurogenesis occurs. If this flow is disrupted, then as our data show, the development of the cortex is seriously affected. Thus, normal cortical development is likely to be critically dependent on not only the presence of CSF, but also its correct flow and composition. There are many lines of evidence that point to CSF having a role in brain development (Sedlacek, 1975; Arnold et al., 1999; Dziegielewska et al., 1980, 1981, 1986; Cavanagh et al., 1982; Xia et al., 2000), as well as its more physiological and mechanical role as a ‘brain buffer’ in the adult (Davson et al., 1987; Piatt, 2001). Constituents of CSF change during development and in response to physiological challenges, and are capable of contacting cells in the cortical parenchyma (Kasaian and Neet, 1989; Suzaki et al., 1997; Mogi et al., 1996; Heinze et al., 1998; Korhonen et al., 1998; Arnold et al., 1999; Van Setten et al., 1999; Biou et al., 2000; Grouzmann et al., 2000; Proescholdt et al., 2000). Manipulation of CSF volume (in chick embryos) or growth factor content (in adult rodents) can result in a failure of normal cortical development and/or hydrocephalus (Johanson et al., 1999; Moinuddin and Tada, 2000).
An interesting aspect of the data presented here is that the blockage of cell cycle by affected H-Tx CSF appears to be at the S or G2-M phase. Blockage at this stage of the cycle is usually associated with the cellular response to DNA damage, resulting in activation of DNA repair or, under extreme damage conditions, apoptosis. Apoptosis is not observed in the GM of the developing cortex of either affected or unaffected H-Tx foetuses or post-natal pups until there is a significant rise in intracranial pressure (this is only observed post-natally) (Miyan et al., 1998). In vitro experiments show that, although the CSF blocks proliferation, it does not result in cell death. The nature of the constituent(s) within the CSF that leads to these effects is thus unusual, as it mediates a novel effect on the cell cycle.
Significantly, the CSF flow pathway also interacts with the marginal zone at the pial surface of the cortex. This area contains the Cajal–Retzius cells which secrete reelin, an extracellular glycoprotein involved in neuronal migration and lamination (D’Arcangelo and Curran, 1998; Rice et al., 1998; Super et al., 2000). An analysis of a number of neurological disorders suggests that CSF signalling may be involved in the control of Cajal–Retzius cells and thus, together with control of neurogenesis, may coordinate the generation, migration and lamination of neurons to the cortex (Clark et al., 1997; Ringstedt et al., 1998; Super et al., 2000; Walsh and Goffinet, 2000).
Our studies on the H-Tx rat have identified a critical role for CSF in cortical development. This fluid is far from being just a buffer for the brain. It is capable of influencing GM cell functionality and disruption of its normal flow pathways leads to abnormal foetal cortical development resulting in significant neurological deficiencies in affected individuals. The potential exists to manipulate the components responsible for abnormal development and aid the developmental process in affected foetuses. Moreover, a greater understanding of the role of CSF in development, particularly neurogenesis, migration and lamination of neurons in the developing cortex could influence the management of other developmental defects of the brain as well as the therapeutic use of neuronal stem cells and/or pharmacological agents.
|
Acknowledgements |
|---|
We wish to thank Janet Wilson-Walsh and Nick Ritchie for technical assistance. This work was funded by a Wellcome Trust grant to J.A.M., J.O-L. and C.M.B.
|
References |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
Arnold PM, Ma JY, Citron BA, Festoff BW. Insulin-like growth factor binding proteins in cerebrospinal fluid during human development and aging. Biochem Biophys Res Commun 1999; 264: 652–6.[CrossRef][Web of Science][Medline]
Biou D, Benoist JF, Nguyen-Thi C, Huong X, Morel P, Marchand M. Cerebrospinal fluid protein concentrations in children: age-related values in patients without disorders of the central nervous system. Clin Chem 2000; 46: 399–403.
Cavanagh ME, Cornelis ME, Dziegielewska KM, Luft AJ, Lai PC, Lorscheider FL, et al. Proteins in cerebrospinal fluid and plasma of foetal pigs during development. Dev Neurosci 1982; 5: 492–502.[Web of Science][Medline]
Clark GD, Mizuguchi M, Antalffy B, Barnes J, Armstrong D. Predominant localization of the LIS family of gene products to Cajal-Retzius cells and ventricular neuroepithelium in the developing human cortex. J Neuropathol Exp Neurol 1997; 56: 1044–52.[Web of Science][Medline]
D’Arcangelo G, Curran T. Reeler: new tales on an old mutant mouse. [Review]. Bioessays 1998; 20: 235–44.[CrossRef][Web of Science][Medline]
Davson H, Welch K, Segal MB. Physiology and pathophysiology of the cerebrospinal fluid. Edinburgh: Churchill Livingstone; 1987.
Dziegielewska KM, Evans CA, Fossan G, Lorscheider FL, Malinowska DH, Mollgard K, et al. Proteins in cerebrospinal fluid and plasma of foetal sheep during development. J Physiol 1980; 300: 441–55.
Dziegielewska KM, Evans CA, Lai PC, Lorscheider FL, Malinowska DH, Mollgard K, et al. Proteins in cerebrospinal fluid and plasma of foetal rats during development. Dev Biol 1981; 83: 193–200.[CrossRef][Web of Science][Medline]
Dziegielewska KM, Hinds LA, Sarantis ME, Saunders NR, Tyndale-Biscoe CH. Proteins in cerebrospinal fluid and plasma of the pouch young tammar wallaby (Macropus eugenii) during development. Comp Biochem Physiol 1986; 83: 561–7.[CrossRef]
Frim DM, Scott RM, Madsen JR. Surgical management of neonatal hydrocephalus. [Review]. Neurosurg Clin N Am 1998; 9: 105–10.[Web of Science][Medline]
Grouzmann E, Borgeat A, Fathi M, Gaillard RC, Ravussin P. Plasma and cerebrospinal fluid concentration of neuropeptide Y, serotonin, and catecholamines in patients under propofol or isoflurane anesthesia. Can J Physiol Pharmacol 2000; 78: 100–7.[CrossRef][Web of Science][Medline]
Harris NG, Jones HC, Williams SC. MR imaging for measurements of ventricles and cerebral cortex in post-natal rats (H-Tx strain) with progressive inherited hydrocephalus. Exp Neurol 1992; 118: 1–6.[CrossRef][Web of Science][Medline]
Harris NG, McAllister JP 2nd, Conaughty JM, Jones HC. The effect of inherited hydrocephalus and shunt treatment on cortical pyramidal cell dendrites in the infant H-Tx rat. Exp Neurol 1996; 141: 269–79.[CrossRef][Web of Science][Medline]
Hawkins D, Bowers TM, Bannister CM, Miyan JA. The functional outcome of shunting H-Tx rat pups at different ages. Eur J Pediatr Surg 1997; 7 Suppl 1: 31–4.
Heinze E, Boker M, Blum W, Behnisch W, Schulz A, Urban J, et al. GH, IGF-I, IGFBP-3 and IGFBP-2 in cerebrospinal fluid of infants, during puberty and in adults. Exp Clin Endocrinol Diabetes 1998; 106: 197–202.[Web of Science][Medline]
Johanson CE, Jones HC. Promising vistas in hydrocephalus and cerebrospinal fluid research. Trends Neurosci 2001; 24: 631–2.[CrossRef][Medline]
Johanson CE, Szmydynger-Chodobska J, Chodobski A, Baird A, McMillan P, Stopa EG. Altered formation and bulk absorption of cerebrospinal fluid in FGF-2-induced hydrocephalus. Am J Physiol 1999; 277: R263–71.
Johanson C, Del Bigio M, Kinsman S, Miyan J, Pattisapu J, Robinson M, et al. New models for analysing hydrocephalus and disorders of CSF volume transmission. Br J Neurosurg 2001; 15: 281–3.[CrossRef][Medline]
Jones HC. Aqueduct stenosis in animal models of hydrocephalus. Childs Nerv Syst 1997; 13: 503–4.[CrossRef][Web of Science][Medline]
Jones HC, Bucknall RM. Inherited prenatal hydrocephalus in the H-Tx rat: a morphological study. Neuropathol Appl Neurobiol 1988; 14: 263–74.[Web of Science][Medline]
Jones SE, Christie DL, Dziegielewska KM, Hinds LA, Saunders NR. Developmental profile of a fetuin-like glycoprotein in neocortex, cerebrospinal fluid and plasma of post-natal tammar wallaby (Macropus eugenii). Anat Embryol (Berl) 1991; 183: 313–20.[Medline]
Jones HC, Briggs RW, Harris NG. Inherited hydrocephalus in H-Tx rat pups: treatment monitored with magnetic resonance imaging. Eur J Pediatr Surg 1993; 3 Suppl 1: 29–30.
Jones HC, Harris NG, Briggs RW, Williams SC. Shunt treatment at two post-natal ages in hydrocephalic H-Tx rats quantified using MR imaging. Exp Neurol 1995; 133: 144–52.[CrossRef][Web of Science][Medline]
Jones HC, Lopman BA, Jones TW, Carter BJ, Depelteau JS, Morel L. The expression of inherited hydrocephalus in H-Tx rats. Childs Nerv Syst 2000; 16: 578–84.[CrossRef][Web of Science][Medline]
Jones HC, Carter BJ, Depelteau JS, Roman M, Morel L. Chromosomal linkage associated with disease severity in the hydrocephalic H-Tx rat. Behav Genet 2001; 31: 101–11.[CrossRef][Web of Science][Medline]
Kasaian MT, Neet KE. Nerve growth factor in human amniotic and cerebrospinal fluid. Biofactors 1989; 2: 99–104.[Medline]
Kitazawa K, Tada T. Elevation of transforming growth factor-beta 1 level in cerebrospinal fluid of patients with communicating hydrocephalus after subarachnoid hemorrhage. Stroke 1994; 25: 1400–4.[Abstract]
Kohn DF, Chinookoswong N, Chou SM. Animal model of human disease. Congenital hydrocephalus. Am J Pathol 1984; 114: 184–5.[Web of Science][Medline]
Korhonen L, Riikonen R, Nawa H, Lindholm D. Brain derived neurotrophic factor is increased in cerebrospinal fluid of children suffering from asphyxia. Neurosci Lett 1998; 240: 151–4.[CrossRef][Web of Science][Medline]
Mashayekhi F, Draper CE, Bannister CM, Pourghasem M, Owen-Lynch PJ, Miyan JA. Deficient cortical development in the hydrocephalic Texas (H-Tx) rat: a role for CSF. Brain 2002; 125: 1859–74.
Matsumoto S, Tamaki N. Hydrocephalus. Tokyo: Springer-Verlag; 1991.
McAllister JP 2nd, Chovan P. Neonatal hydrocephalus. Mechanisms and consequences. [Review]. Neurosurg Clin N Am 1998; 9: 73–93.[Web of Science][Medline]
Miyan JA, Khan MI, Kawarada Y, Sugiyama T, Bannister CM. Cell death in the brain of the HTx rat. Eur J Pediatr Surg 1998; 8 Suppl 1: 43–8.
Mogi M, Harada M, Narabayashi H, Inagaki H, Minami M, Nagatsu T. Interleukin (IL)-1 beta, IL-2, IL-4, IL-6 and transforming growth factor-alpha levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson’s disease. Neurosci Lett 1996; 211: 13–6.[CrossRef][Web of Science][Medline]
Moinuddin SM, Tada T. Study of cerebrospinal fluid flow dynamics in TGF-beta 1 induced chronic hydrocephalic mice. Neurol Res 2000; 22: 215–22.[Web of Science][Medline]
Nicholson C. Signals that go with the flow. Trends Neurosci 1999; 22: 143–5.[CrossRef][Medline]
Oi S. Hydrocephalus chronology in the fetus: pathophysiology of aqueductal stenosis and morphological findings in animal models. Reply to the letter from Dr H. C. Jones. Childs Nerv Syst 1998; 14: 614–6.[CrossRef][Web of Science][Medline]
Oi S, Yamada H, Sato O, Matsumoto S. Experimental models of congenital hydrocephalus and comparable clinical problems in the foetal and neonatal periods. [Review]. Childs Nerv Syst 1996; 12: 292–302. [CrossRef][Web of Science][Medline]
Piatt JH Jr. Why is there CSF? Pediatr Neurosurg 2001; 35: 283.
Pourghasem M, Mashayekhi F, Bannister CM, Miyan J. Changes in the CSF fluid pathways in the developing rat foetus with early onset hydrocephalus. Eur J Pediatr Surg 2001; 11 Suppl 1: S10–3.
Proescholdt MG, Hutto B, Brady LS, Herkenham M. Studies of cerebrospinal fluid flow and penetration into brain following lateral ventricle and cisterna magna injections of the tracer [14C]inulin in rat. Neuroscience 2000; 95: 577–92.[Web of Science][Medline]
Rekate HL. Recent advances in the understanding and treatment of hydrocephalus. [Review]. Semin Pediatr Neurol 1997; 4: 167–78.[CrossRef][Medline]
Rice DS, Sheldon M, D‘Arcangelo G, Nakajima K, Goldowitz D, Curran T. Disabled-1 acts downstream of Reelin in a signaling pathway that controls laminar organization in the mammalian brain. Development 1998; 125: 3719–29.[Abstract]
Ringstedt T, Linnarsson S, Wagner J, Lendahl U, Kokaia Z, Arenas E, et al. BDNF regulates reelin expression and Cajal-Retzius cell development in the cerebral cortex. Neuron 1998; 21: 305–15.[CrossRef][Web of Science][Medline]
Schoniger S, Kopp MD, Schomerus C, Maronde E, Dehghani F, Meiniel A, et al. Effects of neuroactive substances on the activity of subcommissural organ cells in dispersed cell and explant cultures. Cell Tissue Res 2002; 307: 101–14.[CrossRef]
Sedlacek J. Development of the cerebrospinal fluid in chick embryos. Physicochemical properties. Physiol Bohemoslov 1975; 24: 229–37.
Super H, Del Rio JA, Martinez A, Perez-Sust P, Soriano E. Disruption of neuronal migration and radial glia in the developing cerebral cortex following ablation of Cajal–Retzius cells. Cereb Cortex 2000; 10: 602–13.
Suzaki I, Hara T, Maegaki Y, Narai S, Takeshita K. Nerve growth factor levels in cerebrospinal fluid from patients neurologic disorders. J Child Neurol 1997; 12: 205–7.
Van Setten GB, Edstrom L, Stibler H, Rasmussen S, Schultz G. Levels of transforming growth factor alpha (TGF-alpha) in human cerebrospinal fluid. Int J Dev Neurosci 1999; 17: 131–4.[CrossRef][Web of Science][Medline]
Walsh CA, Goffinet AM. Potential mechanisms of mutations that affect neuronal migration in man and mouse. [Review]. Curr Opin Genet Dev 2000; 10: 270–4.[CrossRef][Web of Science][Medline]
Xia YX, Ikeda T, Xia XY, Ikenoue T. Differential neurotrophin levels in cerebrospinal fluid and their changes during development in newborn rat. Neurosci Lett 2000; 280: 220–2.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  B. Nait-Oumesmar, N. Picard-Riera, C. Kerninon, L. Decker, D. Seilhean, G. U. Hoglinger, E. C. Hirsch, R. Reynolds, and A. Baron-Van Evercooren Activation of the subventricular zone in multiple sclerosis: Evidence for early glial progenitors PNAS, March 13, 2007; 104(11): 4694 - 4699. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Nagra, L. Koh, A. Zakharov, D. Armstrong, and M. Johnston Quantification of cerebrospinal fluid transport across the cribriform plate into lymphatics in rats Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2006; 291(5): R1383 - R1389. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. Lowery and H. Sive Initial formation of zebrafish brain ventricles occurs independently of circulation and requires the nagie oko and snakehead/atp1a1a.1 gene products Development, May 1, 2005; 132(9): 2057 - 2067. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||