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Neuropeptide signaling and hydrocephalus: SCO with the flow
David J. Picketts
Molecular Medicine Program, Ottawa Health Research Institute, and Department of Medicine, Department of Biochemistry, Microbiology, and Immunology, and Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario, Canada.
Address correspondence to: David Picketts, Ottawa Health Research Institute, 501 Smyth Road, Ottawa, Ontario K1H8L6, Canada. Phone: (613) 737-8989; Fax: (613) 737-8803; E-mail: dpicketts@ohri.ca .
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Published July 3, 2006 - More info
J Clin Invest. 2006;116(7):1828–1832. https://doi.org/10.1172/JCI29148.
© 2006 The American Society for Clinical Investigation
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Abstract
Hydrocephalus is a common and potentially devastating birth defect affecting the CNS, and its relationship with G protein–coupled receptors (GPCRs) is unknown. We have expressed 2, 4, or 6 copies of a GPCR — the human PAC1 receptor with a 130-kb transgene in the mouse nervous system in a pattern closely resembling that of the endogenous gene. Consistent with PAC1 actions, PKA and PKC activity were elevated in the brains of Tg mice. Remarkably, Tg mice developed dose-dependent hydrocephalus-like characteristics, including enlarged third and lateral ventricles and reduced cerebral cortex, corpus callosum, and subcommissural organ (SCO). Neuronal proliferation and apoptosis were implicated in hydrocephalus, and we observed significantly reduced neuronal proliferation and massively increased neuronal apoptosis in the developing cortex and SCO of Tg embryos, while neurite outgrowth and neuronal migration in vitro remain uncompromised. Ventricular ependymal cilia are crucial for directing cerebrospinal fluid flow, and ependyma of Tg mice exhibited disrupted cilia with increased phospho-CREB immunoreactivity. These data demonstrate that altered neuronal proliferation/apoptosis and disrupted ependymal cilia are the main factors contributing to hydrocephalus in PAC1-overexpressing mice. This is the first report to our knowledge demonstrating that misregulation of GPCRs can be involved in hydrocephalus-related neurodevelopmental disorders.
Authors
Bing Lang, Bing Song, Wendy Davidson, Alastair MacKenzie, Norman Smith, Colin D. McCaig, Anthony J. Harmar, Sanbing Shen
Hydrocephalus arises from an accumulation of cerebrospinal fluid (CSF), most frequently due to an impairment of CSF flow within either the ventricular system (noncommunicating hydrocephalus) or the subarachnoid space (communicating hydrocephalus). The CSF is secreted from the choroid plexus, and movement through the ventricular system occurs in a rostrocaudal direction, from the lateral ventricles to the third ventricle via the foramen of Munro, then through the Sylvian aqueduct to the fourth ventricle, and finally into the cisterna magna of the subarachnoid space and the central canal of the spinal cord (Figure 1). Ultimately, CSF fluid is removed through the arachnoid villi into the venous circulation.
Figure 1CSF flow and the SCO. CSF is secreted from the choroid plexus and travels through the ventricular system in a rostrocaudal direction from the lateral ventricles to the third ventricle via the foramen of Munro, then through the Sylvian aqueduct to the fourth ventricle, and finally into the cisterna magna of the subarachnoid space and the central canal of the spinal cord. CSF fluid is removed through the arachnoid villi into the venous circulation.
Noncommunicating hydrocephalus results from an obstruction of the ventricular system and has many causes, including viral infection, tumors, hemorrhage, and developmental defects (1). Obstruction usually occurs in the narrowed segments of the ventricular system, typically the cerebral aqueduct. Indeed, stenosis of the cerebral aqueduct is considered the primary cause of congenital hydrocephalus (1, 2). Several factors play a role in the maintenance of CSF flow through the narrow canals, including ciliary movement on ependymal cells and a functioning subcommissural organ (SCO), an ependymal gland located in the dorsocaudal region of the third ventricle at the entrance of the Sylvian aqueduct (Figure 2) (3, 4). It is well established that the SCO secretes glycoproteins that aggregate and form a long, threadlike structure known as Reissner’s fiber (RF) in most vertebrate species (Figure 2). RF elongates and extends through the Sylvian aqueduct to the central canal of the spinal cord and prevents closure of the aqueduct while maintaining CSF flow (4–6). Although such a threadlike fiber has not been found in humans, there is evidence of secreted glycoproteins that remain soluble; these are thought to facilitate flow through the aqueduct (7). Moreover, malformation of the SCO has been identified in several rat and mouse strains that develop spontaneous hydrocephalus (8–10) and in transgenic mouse strains in which the expression of specific genes have been altered (11–14). In this regard, the article by Lang et al. in this issue of the JCI confirms the importance of the SCO in the development of hydrocephalus and implicates the pituitary adenylate cyclase–activating polypeptide (PACAP) neuropeptide signaling cascade in the process (15).
Figure 2Schematic diagram modeling flow through the Sylvian aqueduct in WT and PAC1 receptor transgenic mice. (A) In WT mice, ependymal cells from the SCO secrete glycoproteins that form RF and help maintain laminar flow of the CSF through the aqueduct. Cilia on the vel cells also promote CSF flow. (B) In transgenic animals, there are fewer SCO cells, which may result in absent or disorganized RF but not stenosis of the aqueduct. In addition, shorter, inefficient cilia are present on the vel cells. Together, these defects likely result in turbulent CSF flow at the entrance (curved arrows) and reduced flow within (dashed arrows) the cerebral aqueduct, thereby promoting hydrocephalus.
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PAC1 receptor and the development of the SCO
A common feature in animal models of hydrocephalus is the lack of SCO or an abnormally developed SCO (reviewed in refs. 1, 3). Such an observation was also made by Lang et al. (15); the size and cell number of the SCO were dramatically reduced through enhanced apoptosis. Mouse and rat mutants that spontaneously develop hydrocephalus and present with malformed SCO often develop stenosis of the aqueduct (1). However, the PAC1 transgenic mice showed an enlarged aqueduct, suggesting that the underlying mechanism may be different (see Figure 4 in ref. 15).
As the PAC1 receptor is normally expressed in the cells of the SCO, it implies that PACAP signaling may normally regulate the secretion of glycoproteins into the CSF through PKA or PKC signaling conduits (Figure 3). Overproduction of secreted glycoproteins may lead to aggregate accumulation at the entrance of the aqueduct that could result in turbulent or reduced flow of the CSF through the canal. Consistent with such a mechanism is the finding that PACAP signaling stimulates insulin secretion (18). Moreover, analysis of the SCO in the hyh mouse mutant showed an increase in secretory activity (8). Alternatively, if PACAP signaling inhibited glycoprotein secretion, it may interfere with the correct formation of RF and with CSF flow. This latter possibility seems less likely, since the absence of the RF often leads to stenosis of the aqueduct, which was not observed. A third possibility is that the atrophic SCO leads to deficiencies in the RF such that it cannot properly regulate the monoamine concentration in the CSF. Increased levels of monoamines could feedback to the choroidal cells of the choroid plexus, resulting in increased CSF production. Additional experiments are required to determine the normal effect of PACAP signaling on the function of the ependymal cells of the SCO and the subsequent formation of the RF.
Figure 3Potential mechanisms of increased PAC1 receptor signaling. Schematic representation of PACAP/PAC1 receptor signaling through the PKA and PKC pathways. AC, adenylyl cyclase; DG, diacylglycerol; IP3, inositol triphosphate; MAPKK, MAPK kinase; MAPKKK, MAPKK kinase.
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