Table 1.
List of the final papers selected for the review.
| Authors | Title | Journal | Methods | Findings |
|---|---|---|---|---|
| Tennyson et al. (4) | An electron microscope study of ependymal cells of the fetal, early postnatal and adult rabbit. | Zeitschrift für Zellforschung und mikroskopische Anatomie. 1962 | Electron microcopy analysis of rabbit ependymal cells. | Simple columnar cell type in the mature rabbit. Ependymal astrocytes and tanycytes are common in embryos. Extensive interdigitations and numerous organelles are present in the latter cellular elements. |
| Duckett (5) | The germinal layer of the growing human brain during early fetal life. | The Anatomical Record. 1968 | Light and electron microscopy of the germinal telencephalon. | The human telencephalon may have an absorptive role between the eighth and fifteenth weeks of fetal life, given its resemblance to the renal epithelium. |
| Fossan et al. (6) | CSF-brain permeability in the immature sheep fetus: a CSF-brain barrier. | Developmental Brain Research. 1985 | Permeability of the neuroependyma between CSF and brain studied in fetal sheep of 60 and 125 days gestation. | Horseradish peroxidase penetration limited to the ventricles in fetuses, but present in the subventricular zone in adults. Lower volumes of distribution of sucrose and insulin in younger animals, with narrower solute distribution. |
| Møllgård et al. (7) | Cell junctions and membrane specializations in the ventricular zone (germinal matrix) of the developing sheep brain: a CSF-brain barrier. | Journal of neurocytology. 1987 | Electron microscopy of neuroependymal cells at day 19–40 of embryonic development. | Continuos tight and gap junctions were identified in the earliest stages, with tight junction spiraling from the ventricular pole toward the deeper ventricular zone. Zonulae adherents, large gap junctions and orthogonal arrays were found in mature ependyma. |
| Møllgård et al. (7) | The development of the human blood-brain and blood-CSF barriers. | Neuropathology and applied neurobiology. 1986 | Horseradish peroxidase and freeze-fracturing in chick, rat and monkey brain. | High CSF protein concentration in the fetal ventricles. Strap junctions were found in the developing germinal matrix. |
| Brightman and Reese (8) | Junctions between intimately apposed cell membranes in the vertebrate brain. | The Journal of cell biology. 1969 | Horseradish peroxidase and lanthanum | Penetration of horseradish peroxidase or lanthanum in the median gap, suggesting the existence of gap junctions and incomplete tight junctions. |
| Cavanagh and Warren (9) | The distribution of native albumin and foreign albumin injected into lateral ventricles of prenatal and neonatal rat forebrains. | Anatomy and embryology. 1985 | Distribution of plasma albumin in the rat forebrain from day 14 of gestation until birth. | Not seen within cells of the developing forebrain until day 16E or 17E. Sheep albumin was taken up rapidly into cells of the ventricular zone at the later but not the earlier ages, suggesting uptake rather than local synthesis. |
| Dziegielewska et al. (10) | Proteins in cerebrospinal fluid and plasma of fetal rats during development. | Developmental biology. 1981 | Total protein, albumin, and α-fetoprotein measured in CSF and plasma of fetal (12 to 22 days gestation) and neonatal (0 to 10 days postnatal) rats | Total protein concentration in plasma increased throughout the developmental period studied as did that of albumin. α-Fetoprotein peaked at day 19 of gestation and then declined. Albumin and α-fetoprotein constituted over 50% of the total protein concentration in csf at all fetal ages. |
| Dziegielewska et al. (10) | Studies of the development of brain barrier systems to lipid insoluble molecules in fetal sheep. | The Journal of physiology. 1979 | Distribution of labeled erythritol (C14), sucrose (3H or 14C), inulin (3H or 14C) and albumin (125I), or albumin and IgG detected by immunoassay in fetal sheep, early (60 days) and late (125 days) in gestation. | 60 days: markers seem to penetrate into CSF by diffusion. Reduction in penetration which occurred by 125 days for all markers except erythritol. No change in junctional characteristics (tight junction depth and strand number) between the two ages studied, despite the changes in permeability. |
| Dziegielewska et al. (10) | Blood-cerebrospinal fluid transfer of plasma proteins during fetal development in the sheep. | The Journal of physiology. 1980 | Penetration of human and sheep plasma proteins from blood into CSF of sheep fetuses (57-86 days gestation) was studies. | CSF:plasma ratios were 15% for hAFP, 10% for hTransferrin and sheep albumin, 7% for hα1-antitrypsin, and 5% for hAlbumin. Reduced penetration of protein from blood into CSF in older fetuses. The immature choroid plexus may allow for transcellulare protein movement, important for some aspects of brain development. |
| Dziegielewska et al. (10) | Proteins in cerebrospinal fluid and plasma of postnatal Monodelphis domestica (gray short-tailed oposum). | Comparative Biochemistry and Physiology Part B: Comparative Biochemistry. 1989 | CSF and plasma protein concentration measured from birth to adulthood. | Total protein in CSF increased from birth to a peak concentration between 5-10 days post-partum. CSF-brain barrier appears to exclude CSF protein from brain extracellular space. |
| Dziegielewska et al. (10) | Proteins in cerebrospinal fluid and plasma of the pouch young tammar wallaby (Macropus eugenii) during development. | Comparative Biochemistry and Physiology Part B: Comparative Biochemistry. 1986 | CSF and plasma protein concentration measured from birth until leaving the pouch. | Total protein in CSF increased from birth to a peak concentration between 15-20 days post-partum. |
| Mack et al. (11) | Relationship between orthogonal arrays of particles and tight junctions as demonstrated in cells of the ventricular wall of the rat brain | Cell and tissue research. 1987 | Ependymal cells in the ventricular wall and circumventricular organs compared with freeze-fracturing. | Ependymal cells have orthogonal arrays of particles (OAP), but not tight junctions. Choroid plexus cells present tight junctions, but not OAPs. In the boundary zone between choroid plexus and ependyma both OAPs and tight junctions coexist. |
| Gotow and Hashimoto (12) | Intercellular junctions between specialized ependymal cells in the subcommissural organ of the rat. | Journal of Neurocytology. 1982 | Permeability of ependymal cells studied with freeze-fracturing and tracer experiments with horseradish peroxidase (HRP). | One or two strands with interruptions in the apical portion of ependymocytes. Intraventricularly infused HRP leaks through junctions but is sometimes stopped. Intercellular spaces of different lengths are found between tight junctions. |
| Rieke et al. (13) | Ultrastructure of ependymal cells in primary cultures of cerebral cortex. | Journal of neuroscience research. 1987 | Electron microscopy of primary ependymal cultures. | Zonula occludens and adherens, membrane interdigitations were noticed in the lateral cell membrane. |
| Whish et al. (14) | The inner CSF–brain barrier: developmentally controlled access to the brain via intercellular junctions. | Frontiers in neuroscience. 2015 | Study of permeability of CSF-brain barrier from embryonic day 17 until adult with multiple probes and proteomic analysis. | At early fetal stages solute movement is restricted to the smallest molecules 286Da, while by postnatal day 20 70kDa probes can diffuse freely. Gap junctions and claudin-11 were found only in adults, while N-cadherin, β - and α-catenin were detected in embryos. |
| Mochida et al. (15) | A homozygous mutation in the tight-junction protein JAM3 causes hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. | The American Journal of Human Genetics. 2010 | Homozygosity mapping and gene sequencing. | Mutation in splice-donor site of intron 5 of JAM3, chromosome 11q25. Responsible for a familial syndrome with hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts secondary to tight junction and ependymal destruction. |
| Drielsma et al. (16) | Two novel CCDC88C mutations confirm the role of DAPLE in autosomal recessive congenital hydrocephalus. | Journal of medical genetics. 2012 | Homozygosity mapping and whole exome sequencing in two families with non-syndromic hydrocephalus | Homozygous mutation in the DAPLE encoding for CCDC88C. Truncated extreme C-terminus of DAPLE that binds Dlg1 and zo-1, with ependyma collapse. |
| Saugier-Veber et al. (17) | Hydrocephalus due to multiple ependymal malformations is caused by mutations in the MPDZ gene. | Acta neuropathologica communications. 2017 | Post-mortem homozygosity mapping and whole exome sequencing in 3 fetuses. | Three novel homozygous null mutations in the MPDZ gene in fetuses with multiple ependymal malformations. MPDZ is a component of tight junctions of the ependyma/choroid plexus. |
| Feldner et al. (18) | Loss of Mpdz impairs ependymal cell integrity leading to perinatal-onset hydrocephalus in mice. | EMBO molecular medicine. 2017 | Generation of mouse models of Mpdz deletion. | Mpdz gene deletion/conditional inactivation in Nestin-positive cells in mouse models led to hydrocephalus. Ependymocytes with normal tight junctions, but diminished expression of the planar cell polarity protein Pals1. Ependymal denudation with gliosis and aqueductal stenosis/hydrocephalus. |
| Yang et al. (19) | Murine MPDZ-linked hydrocephalus is caused by hyperpermeability of the choroid plexus. | EMBO molecular medicine. 2019 | MRI and comparative proteomic analysis of CSF content in normal and MPDZ LOF animals. | Humans and mice with a truncated version of MPDZ develop severe hydrocephalus and death. Contrast penetration is noticed on MRI in animals with MPDZ loss of function, with increased transcytosis and paracellular permeability. |
| Petrov et al. (20) | Distribution of the tight junction-associated protein ZO-1 in circumventricular organs of the CNS. | Molecular brain research. 1994 | Study of immunofluorescent distribution of ZO-1 in murine circumventricular organs. | Unbroken ZO-1 distribution in specialized ependymal cells adjacent to organum vasculosum laminae terminalis and subcommissural organ. Heterogeneous ZO-1 staining pattern in blood vessels and ventricular walls. |
| Kang et al. (21) | Effect of estrogen on the expression of occludin in ovariectomized mouse brain. | Neuroscience letters. 2006 | Expression of occludin in ovariectomized female brain was studied with IHC, WB and mRNA sequencing. | Decrease in occludin expression in ovariectomized mice. 17β estradiol up-regulates occludin mRNA levels. |
| Steinemann et al. (22) | Claudin-1,-2 and-3 are selectively expressed in the epithelia of the choroid plexus of the mouse from early development and into adulthood while claudin-5 is restricted to endothelial cells. | Frontiers in neuroanatomy. 2006 | Study of claudin expression in the choroid plexus and ependymal regions around the plexuses via IHC with novel fixation and alkaline phosphatase detection system. | Significant claudin-1, - 2, - 3 expression in choroidal cells and surrounding ependyma. |
| Alvarez and Teale (23) | Differential changes in junctional complex proteins suggest the ependymal lining as the main source of leukocyte infiltration into ventricles in murine neurocysticercosis. | Journal of neuroimmunology. | Analysis of junctional complexes of animals infected with Mesocestoides corti. | Reduction in ependymal occludin expression with increased leukocyte and microbial transmigration and infection spread. |
| Oliver et al. (24) | Disruption of CDH2/N-cadherin-based adherens junctions leads to apoptosis of ependymal cells and denudation of brain ventricular walls. | Journal of Neuropathology & Experimental Neurology. 2013 | Blockage of N-cadherin function in cellular and mouse models. | Disruption of zonula adherens, abnormal intracellular accumulation of N-cadherin, ependymal denudation and obstructive hydrocephalus. |
| Hatta et al. (25) | Spatial and temporal expression pattern of N-cadherin cell adhesion molecules correlated with morphogenetic processes of chicken embryos. | Developmental biology. 1987 | Immunohistochemistry for N-cadherin in chicken embryos. | Disappearance of N-cadherin is correlated with rearrangement, segregation, or association of cells. N-cadherin expression is related to L-CAM cellular expression. |
| Gänzler-Odenthal et al. (26) | Blocking N-cadherin function disrupts the epithelial structure of differentiating neural tissue in the embryonic chicken brain. | Journal of Neuroscience. 1998 | N-cadherin blockage during early chicken brain development. | Invaginations of ependymal lining, formation of neuroepithelial rosettes and multiple ependymal layers in the tectum and dorsal thalamus |
| Sival et al. (27) | Neuroependymal denudation is in progress in full-term human fetal spina bifida aperta. | Brain pathology. 2011 | Immunostaining for ependymal markers (caveolin 1, βIV-tubulin, S100), junction proteins (N-cadherin, connexin-43, NCAM), blood vessels (Glut-1) and astrocytes (GFAP) in control and Spina Bifida Aperta fetuses. | Four stages of ependymal denudation and failure were observed in Spina Bifida patients, with formation of pseudorosettes. Abnormalities in gap and adherent junctions cause defective ependymal coupling, desynchronized ciliary beating and ependymal denudation. |
| Guerra et al. (28) | Defects in cell-cell junctions lead to neuroepithelial/ependymal denudation in the telencephalon of human hydrocephalic fetuses. | Cerebrospinal Fluid Research. 2010 | Immunocytochemistry with antibodies against N-cadherin and connexin-43, bIV-tubulin bIII-tubulin markers in hydrocephalic and SBA fetuses. | Denuded and altered ependymal areas associated with abnormal N-cadherin expression, rosettes and periventricular heterotopias. |
| Nechiporuk et al. (29) | Failure of epithelial tube maintenance causes hydrocephalus and renal cysts in Dlg5–/– mice. | Developmental cell. 2007 | RT-PCR and sequencing of Napa in hyh-mutated mice. | hyh mice carry a mutation in Napa encoding soluble NSF attachment for αSnap. This leads to abnormal localization of E-cadherin, β-catenin, atypical protein kinase C (aPKC) and INADL. |
| Jiménez et al. (30) | A programmed ependymal denudation precedes congenital hydrocephalus in the hyh mutant mouse. | Journal of Neuropathology & Experimental Neurology. 2001 | Immunocytochemistry and scanning electron microscopy of hyh mice at different stages of development. | Ependymal denudation and aqueductal obstruction starting at embryonic day 12. The authors hypothesized the onset of abnormalities in cell adhesion molecules. |
| Páez et al. (31) | Patterned neuropathologic events occurring in hyh congenital hydrocephalic mutant mice. | Journal of Neuropathology & Experimental Neurology. 2007 | Hyh mice studied with lectin binding, bromodeoxyuridine labeling, immunochemistry, and scanning electron microscopy. | E12 ependymal denudation triggered proliferation of neighboring astrocytes. Abnormalities of the corpus callosum and hippocampal commissure. Alterations developed when hydrocephalus was not yet patent, suggesting hyh causes alterations in neural development. |
| Roales-Buján et al. (32) | Astrocytes acquire morphological and functional characteristics of ependymal cells following disruption of ependyma in hydrocephalus. | Acta neuropathologica. 2012 | Electron microscopy, immunocytochemistry (N-cadherin, connexin 43, aquaporin 4, caveolin-1, EEA1. HRP and lanthanum nitrate used to track transcellular and paracellular routes. | Astrocytes share several features with normal ependyma, such as microvilli, gap junctions, expression of aquaporin 4, caveolin-1 and EEA-1. The also show similar behavior in the paracellular route of molecules/water between CSF, the subependymal neuropile and pericapillary space. |
| Baeza et al. (33) | IIIG9 inhibition in adult ependymal cells changes adherens junctions structure and induces cellular detachment. | Scientific reports. 2021 | Expression and localization of IIIG9 in the adherens junctions (cadherin/β-catenin-positive junctions) of ependymal cells with confocal and electron microscopy. | Ependymal cells with a “balloon-like” morphology. Reduced cadherin, cleavage of caspase-3, “cilia rigidity” and ventriculomegaly occurring prior to these events. IIG9 is essential for the maintenance of adherens junctions. |
| Klezovitch et al. (34) | Loss of cell polarity causes severe brain dysplasia in Lgl1 knockout mice. | Genes & development. 2004 | Histology and immunohistochemistry of Lgl1 knockout mice. | Loss of Lgl1 in mice with formation of neuroepithelial rosettes. Lgl1–/– neural progenitor cells fail to exit the cell cycle and die by apoptosis. Mice develop hydrocephalus and die. This may be explained by incorrect localization of Numb, inhibitor of Notch. |
| Imai et al. (35) | Inactivation of aPKCλ results in the loss of adherens junctions in neuroepithelial cells without affecting neurogenesis in mouse neocortex. | Development. 2006 | Nestin-Cre mediated conditional gene targeting system in aPKCλ ko mice. | Loss of adherens junctions, retraction of apical processes and impaired interkinetic nuclear migration in ependymal cells at E15. Neurogenesis was not affected. |
| Ma et al. (36) | Loss of cell adhesion causes hydrocephalus in nonmuscle myosin II-B–ablated and mutated mice. | Molecular biology of the cell. 2007 | Ablation of NM II-B or replacement with decreased amounts of mutant (R709C), motor-impaired form in mice | Mesh-like structure present at the apical border of ependymocytes containing NM II-B, β-catenin and N-cadherin, with a role in cell adhesion. Mesh-like structure, canal patency and hydrocephalus can be restored by increasing expression of NM II-B. |
| Tullio et al. (37) | Structural abnormalities develop in the brain after ablation of the gene encoding nonmuscle myosin II-B heavy chain. | Journal of Comparative Neurology. 2001 | Ablation of nonmuscle myosin heavy chain II-B (NMHC-B) in mice. | Severe congenital hydrocephalus secondary to disruption of the ventricular surface and cell migration. Formation of rosettes and aqueductal obstruction. |
| Bátiz et al. (38) | Heterogeneous expression of hydrocephalic phenotype in the hyh mice carrying a point mutation in α-SNAP. | Neurobiology of disease. 2006 | hyh mouse carrying a mutation for α-SNAP and light and electron microscopy. | 70% of animals with rapidly progressing hydrocephalus, 30% with slowly progressing hydrocephalus and spontaneous ventriculostomies between the ventricles and the SAH that allowed them to survive. |
| Bátiz et al. (38) | A simple PCR-based genotyping method for M105I mutation of alpha-SNAP enhances the study of early pathological changes in hyh phenotype. | Molecular and cellular probes. 2009 | High-throughput genotyping of hyh mice, to correlate genotype-phenotype, the earliest pathological changes of hyh mutant mice. | Single-gene autosomal recessive disorder with 100% penetrance causing altered membrane trafficking and hydrocephalus. |
| Fabbiani et al. (39) | Connexin signaling is involved in the reactivation of a latent stem cell niche after spinal cord injury. | Journal of Neuroscience. 2020 | Patch-clamping of ependymal cells with ICH for connexins in neonatal and adult normal vs. injured spinal cord mice. | Coupling decreases with postnatal development but increases again after SCI. increase in connexin 26, proliferation and reduction of connexin hemichannel activity were also noticed in the spinal central canal. |
| Bouillé et al. (40) | Gap junctional intercellular communication between cultured ependymal cells, revealed by lucifer yellow CH transfer and freeze-fracture. | Glia. 1991 | Study of gap junctions in primary cultures from fetal mouse or rat hypothalamus and choroid plexus. Transfer of Lucifer Yellow CH after intracellular microinjection and freeze-fracture. | Gap junctional transfer of dye present in ciliated ependymal cells, choroidal ependymocytes and non-choroidal ependymocytes. No dye movement in astrocytes. |
First author's name, article's title, journal, methodology used, and main findings are presented in the table. Papers are subdivided by type of junction investigated. Multiple papers focused on more than one junction type—assignment was based on the main type of junction found by the investigators. Gray, non-specific cellular junctions; yellow, tight junctions; blue, adherens junctions; green, gap junctions.