Role of the subcommissural organ in the pathogenesis of congenital hydrocephalus in the HTx rat

Abstract

The present investigation was designed to clarify the role of the subcommissural organ (SCO) in the pathogenesis of hydrocephalus occurring in the HTx rat. The brains of non-affected and hydrocephalic HTx rats from embryonic day 15 (E15) to postnatal day 10 (PN10) were processed for electron microscopy, lectin binding and immunocytochemistry by using a series of antibodies. Cerebrospinal fluid (CSF) samples of non-affected and hydrocephalic HTx rats were collected at PN1, PN7 and PN30 and analysed by one- and two-dimensional electrophoresis, immunoblotting and nanoLC-ESI-MS/MS. A distinct malformation of the SCO is present as early as E15. Since stenosis of the Sylvius aqueduct (SA) occurs at E18 and dilation of the lateral ventricles starts at E19, the malformation of the SCO clearly precedes the onset of hydrocephalus. In the affected rats, the cephalic and caudal thirds of the SCO showed high secretory activity with all methods used, whereas the middle third showed no signs of secretion. At E18, the middle non-secretory third of the SCO progressively fused with the ventral wall of SA, resulting in marked aqueduct stenosis and severe hydrocephalus. The abnormal development of the SCO resulted in the permanent absence of Reissner's fibre (RF) and led to changes in the protein composition of the CSF. Since the SCO is the source of a large mass of sialilated glycoproteins that form the RF and of those that remain CSF-soluble, we hypothesize that the absence of this large mass of negatively charged molecules from the SA domain results in SA stenosis and impairs the bulk flow of CSF through the aqueduct.

Ciliogenesis and cerebrospinal fluid flow in the developing Xenopus brain are regulated by foxj1

“…Aqueduct stenosis preceding the occurrence of hydrocephalus has been described in rats in which the formation of RF by the SCO was manipulated [44]. This notion was recently supported by an analysis of rats with morphological and functional deficiency of the SCO [45]. RF is thought to keep the aqueduct open, and manipulations interfering with secretion or aggregation of RF-glycoproteins lead to collapse of the aqueduct and subsequent hydrocephalus in late postnatal stages.…”

The origins of the circumventricular organs

“…; Ortloff et al. ). A role in regulating neurogenesis has been suggested for the soluble factors secreted by the SCO (Guerra et al.…”

Blood–brain barrier and foetal-onset hydrocephalus, with a view on potential novel treatments beyond managing CSF flow

“…The SCO differentiates very early in ontogeny and remains fully active during the entire life span, secreting SCO-spondin to the CSF where it either assembles to form Reissner’s fiber (RF) or remains soluble and circulates throughout the CSF compartments [148, 149]. The RF, extending through the Sylvius aqueduct (SA), fourth ventricle and central canal of the spinal cord, is indispensable for maintaining the patency of the SA and the normal flow of CSF [150–152]. An inborn defect of the SCO results in hydrocephalus [137, 138, 152].…”

“…The RF, extending through the Sylvius aqueduct (SA), fourth ventricle and central canal of the spinal cord, is indispensable for maintaining the patency of the SA and the normal flow of CSF [150–152]. An inborn defect of the SCO results in hydrocephalus [137, 138, 152]. …”