Loss of Developmental Factors Impairs SCO Formation and Function

lifeline for supplying the brain with essential nutrients and growth factors throughout development and into adulthood. At the same time, the brain exercises constant control to ensure that the flow of CSF is homeostatic. CSF is secreted by the choroid plexus and moves rostrocaudally through the ventricles and into the subarachnoid space before being drained into the venous circulation (80). Failures within this cerebral irrigation network can lead to a buildup of CSF in the ventricular cavities of the brain, a condition known as hydrocephaly, which is fatal without surgical intervention. Hydrocephalus can result from an overproduction of CSF by the choroid plexus, failure to drain the CSF at the subarachnoid space, and the blockage of CSF flow through the narrow Sylvian aqueduct, which is situated between the third and fourth ventricles. Indeed, stenosis of the Sylvian aqueduct is considered the primary cause of congenital hydrocephalus, which is quite frequent, occurring with an incidence of 0.1–0.3% of live births (80). The causes for this disease are quite heterogeneous and have been linked to a number of genetic mutations, both autosomal and X-linked (112). What is intriguing, though, is that many of these mutations impinge on the development or function of the subcommissural organ (SCO) and the ventricular ependymal (vel) cells that collectively facilitate the flow of CSF through the confining canals of the ventricular system (Table 1). The goal of this review is to summarize the molecular mechanisms that cause 1) the SCO to be absent or disorganized, 2) an inability of the SCO to properly secrete glycoproteins, 3) primary ciliary dyskinesia (PCD) of the ependymal cells, and 4) denudation of the neuroependyma. Although it should be noted that not all SCO/vel defects have been proven to precede the onset of hydrocephaly, indeed it is the aberrant execution of these diverse molecular pathways that can lead to stenosis of the aqueduct and contribute to communicating or noncommunicating hydrocephalus. Loss of Developmental Factors Impairs SCO Formation and Function