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Background The subcommissural organ (SCO) differentiates early in ontogeny and remains fully active during the entire life span. It secretes glycoproteins into the cerebrospinal fluid (CSF) flowing through the Sylvius aqueduct (SA); these proteins either assemble to form Reissner fiber (RF), or remain soluble in the CSF and circulate throughout the CSF compartments. Overholser et al. (1954) have demonstrated that offspring littered by rats maintained on a diet deficient in folic acid and/or Vitamin B12 lack a SCO and develop hydrocephalus. This led them to propose that a dysfunction of the SCO during development leads to stenosis of the SA and hydrocephalus. We have investigated several animal models in which the SCO would play a role in the pathogenesis of hydrocephalus. We have now performed a comparative analysis of the changes occurring in the SCO-RF complex of these animal models, with the aim to find a landmark common to all hydrocephalic animals that might help to unfold the mechanism of SCO-dependant hydrocephalus. Materials and methods A comparative study of the SCO-RF complex and SA of five animal models characterized by a dysfunction of the SCO and development of hydrocephalus was carried out. Conventional light and electron microscopy and immunocytochemistry were applied. Results Model 1. Immunological blockage of RF formation by maternal transfer of antibodies against RF-glycoproteins: undamaged and secretory active SCO, missing RF, stenosed SA and moderate hydrocephalus. Model 2. hyh mice with a point mutation of aSNAP gene: undamaged and secretory active SCO, missing RF, obliterated SA and severe hydrocephalus. Model 3. HTx rat: subcommissural portion (two distal thirds) of SCO missing, supracommissural portion (rostral third) of SCO secretory active, RF absent, obliterated SA and severe hydrocephalus. Model 4. Transgenic mice deficient in transcription factor RFX4- v3: subcommissural portion of SCO missing, supracommissural portion of SCO secretory active, RF absent, patent SA and moderate to severe hydrocephalus. Model 5. fyn knockout mice: subcommissural portion of SCO missing, supracommissural portion of SCO secretory active, RF absent, SA with an abnormal shape and severe hydrocephalus. Conclusion 1. The SCO is formed by two zones: the subcommissural and the supracommissural portions. 2. Differentiation of both zones would be controlled by different genes. 3. The subcommissural portion of the SCO is essential for RF formation. Mutant and transgenic animals lacking this portion, although still have a secretory active flow of CSF throughout SA. 6. Absence of RF could cause SA obliteration or a turbulent CSF flow through SA what, in turn, would lead to hydrocephalus. Supported by Fondecyt 1030265 (Chile), the Intramural Program of the NIH, NIEHS (USA), and MEXT (Japan). [ABSTRACT FROM AUTHOR]

Background There is strong evidence associating a dysfunction of the subcommissural organ (SCO) with the pathogenesis of fetal onset hydrocephalus. In the HTx rat, obliteration of Sylvius (SA) and dilatation of the lateral ventricles start to occur at around E18. This rat animal model of fetal onset hydrocephalus has been the subject of numerous investigations. However, the mechanism and sequence of neuropathological events leading to SA obliteration are not known. The aim of the present investigation is to clarify the role actually played by the SCO in the obliteration of SA. Materials and methods The brain of normal and hydrocephalic E15, E16, E17, E18, E19, E20, E21, PN1, PN3, PN5, PN7 and PN10 H-Tx rats was processed for: (1) immunocytochemistry using antibodies against (i) the secretory proteins of the SCO (AFRU), (ii) nestin and (iii) ciliated ependyma; (2) Limax flavus agglutinin (LFA; affinity = sialic acid) binding; (3) transmission and scanning electron microscopy. Results Up to E18, all embryos from the same litter have a patent SA. However, some of these embryos, most likely corresponding to the mutants that will develop hydrocephalus, displayed an abnormal SCO. The cephalic third and the caudal third of the SCO were strongly immunoreactive with AFRU, anti-nestin and strongly bound LFA. The middle third of the SCO did not react with AFRU and antinesting and LFA binding was weak. At E18 the middle, non-secretory, third of the SCO progressively fused with the opposing region of the ventral wall of SA, resulting in the SA obliteration detected from E19 on. Conclusion 1. In the rostro-caudal axis, the SCO is formed by three distinct zones whose differentiation would be controlled by different genes. 2. A malformation of one of these zones precedes the obliteration of SA. 3. Such a malformation is the primary cause of SA obliteration. [ABSTRACT FROM AUTHOR]