SCO-ping Out the Mechanisms Underlying the Etiology of Hydrocephalus

Abstract

The heterogeneous nature of congenital hydrocephalus has hampered our understanding of the molecular basis of this common clinical problem. However, disease gene identification and characterization of multiple transgenic mouse models has highlighted the importance of the subcommissural organ (SCO) and the ventricular ependymal (vel) cells. Here, we review how altered development and function of the SCO and vel cells contributes to hydrocephalus.

Dysregulation of Kruppel-like factor 4 during brain development leads to hydrocephalus in mice

“…These glycoproteins aggregate and form the threadlike RF, which extends along the length of the CSF tract to the ampulla caudalis. The SCO-RF structure plays a critical role in CSF flow and reabsorption through the Sylvian aqueduct (17). Malformation of the SCO has been implicated in the etiology of hydrocephalus in multiple transgenic mouse strains (30,(35)(36)(37).…”

“…Although the precise molecular mechanism for this brain defect is not yet clear, multiple transcriptional regulators have been implicated. These factors include Engrailed 1, Msx1, E2F5, RFX3, RFX4, Foxj1/Hfh-4, and polymerase λ (17). Based on our current data, KLF4 can now be added to this growing list of factors whose dysregulation may lead to hydrocephalus.…”

Nuclear Factor κB Activation Impairs Ependymal Ciliogenesis and Links Neuroinflammation to Hydrocephalus Formation

“…This process is usually accompanied by activation of ventricular macrophages (Ulfig et al, 2004;Domínguez-Pinos et al, 2005), an issue that is phenocopied in our model system. Several mouse models provide evidence that ependymal defects, in particular impaired cilia function, are involved in hydrocephalus formation (Huh et al, 2009;Del Bigio, 2010). However, the relevance of these models for human hydrocephalus is still under debate, as there are cases known showing on the one hand a partial loss of ependymal integrity and ciliopathies but on the other hand are rarely associated with hydrocephalus (Huh et al, 2009;Del Bigio, 2010).…”

“…Several mouse models provide evidence that ependymal defects, in particular impaired cilia function, are involved in hydrocephalus formation (Huh et al, 2009;Del Bigio, 2010). However, the relevance of these models for human hydrocephalus is still under debate, as there are cases known showing on the one hand a partial loss of ependymal integrity and ciliopathies but on the other hand are rarely associated with hydrocephalus (Huh et al, 2009;Del Bigio, 2010). So far, it is unclear whether defects in ependymal ciliogenesis are involved in the development of human hydrocephalus that is associated with elevated IKK/NF-B signaling in course of infections or intracerebral hemorrhages.…”

“…4 A, top panels), thus classifying this phenotype as a communicating hydrocephalus. The subcommissural organ, whose malformation or loss is thought to be responsible for hydrocephalus formation in some mouse models (Huh et al, 2009), also did not show obvious defects (Fig. 4 A, bottom panels).…”