Chapter two - The Subcommissural Organ and the Development of the Posterior Commissure

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Abstract

Growing axons navigate through the developing brain by means of axon guidance molecules. Intermediate targets producing such signal molecules are used as guideposts to find distal targets. Glial, and sometimes neuronal, midline structures represent intermediate targets when axons cross the midline to reach the contralateral hemisphere. The subcommissural organ (SCO), a specialized neuroepithelium located at the dorsal midline underneath the posterior commissure, releases SCO-spondin, a large glycoprotein belonging to the thrombospondin superfamily that shares molecular domains with axonal pathfinding molecules. Several evidences suggest that the SCO could be involved in the development of the PC. First, both structures display a close spatiotemporal relationship. Second, certain mutants lacking an SCO present an abnormal PC. Third, some axonal guidance molecules are expressed by SCO cells. Finally, SCO cells, the Reissner's fiber (the aggregated form of SCO-spondin), or synthetic peptides from SCO-spondin affect the neurite outgrowth or neuronal aggregation in vitro.

Introduction

Wiring of the developing nervous system occurs in a highly ordered way. This process depends on axonal pathfinding mechanisms that allow growing axons to find their final targets. Neuronal growth cones expose receptors that recognize environmental signals, the so-called axonal guidance cues that establish axonal pathways through which large axonal bundles develop. At early stages of development, the earliest axons that travel ahead and establish for the first time the route of a future tract are called pioneer axons and display peculiar characteristics (Easter et al., 1993). After the pioneer axons have formed the first scaffold, other axons follow such pathways and fasciculate with them to generate the tract (Van Vactor, 1998). In the long haul routes, axonal pathfinding progresses in sequential stages by means of regularly positioned sources of axon guidance molecules, referred to as intermediate targets. When axons have to cross to the opposite hemisphere, forming a commissure or a decussation, cell populations located at the midline of the brain represent important intermediate targets in the axonal trajectory (Kaprielian et al., 2001). Glial cells and, to a lesser extent, neuronal cells form part of such midline intermediate targets. Each commissure or decussation has an associated cell population and extracellular matrix (ECM) molecules produced by these cells to control the crossing of axons at the midline. Glial tunnels, the glial wedge, subcallosal sling, glial palisade, and floor plate (FP) are some of these structures (Chedotal and Richards, 2010).

The subcommissural organ (SCO) is a specialized ependymal structure located in the roof plate of the prosomere 1 under the posterior commissure (PC). The SCO is an ancient and phylogenetically conserved structure present throughout vertebrate phyla (Oksche, 1961). SCO ependymal cells synthesize and secrete the SCO-spondin, a high-molecular-mass glycoprotein, which belongs to the thrombospondin superfamily due to the presence of numerous thrombospondin type 1 repeat (TSR) domains (Meiniel, 2001). The SCO-spondin also contains the TSR type 2 domain, which is shared by molecules involved in developmental processes such as R-spondin, F-spondin, and mindin.

Although investigated since the early twentieth century, there is uncertainty about its functional role, albeit different functional hypotheses have been proposed. One of them concerns to the putative relationship of the SCO with the development of central nervous system (CNS) and, more recently, with the axonal guidance. Different evidences have suggested that the SCO is involved in the PC formation. First, there exists a close spatiotemporal relationship between the SCO and the PC during embryonic development. Second, the SCO is located at the dorsal midline, and the role of this region as intermediate target in axonal pathfinding is widely accepted. Third, data from different mutant mice indicate that animals lacking SCO or with SCO alterations fail to form a normal PC. Fourth, the SCO-spondin belongs to the thrombospondin superfamily, sharing type 2 TSR domains with molecules implicated in axonal pathfinding during the development of the nervous system, such as R-spondin, F-spondin, mindin, and semaphorins. Fifth, the SCO-spondin is expressed by two midline structures: the SCO and, transiently, the rostral FP, the latter having a well-known role in axonal guidance. Sixth, in vitro experiments using RF solubilized compounds or synthetic peptides derived from SCO-spondin in different cell culture systems have revealed a potential role of the SCO-spondin in both neuronal aggregation and neurite outgrowth. Last, coculture experiments confronting SCO explants with ventral diencephalic explants, which give rise to axons forming the PC, have shown that SCO cells can exert attractive or repulsive effects on growing axons. Although none of these evidences is unequivocal, they altogether represent substantial information to support the role of the SCO in the development of the PC. Each of these evidences will be revised in detail in this review.

Section snippets

Axon Guidance and the Development of Commissures

The establishment of the neuronal cytoarchitecture and neural circuits is essential for the brain functions. During embryonic development, wiring of the nervous system occurs in a highly patterned and ordered manner. This means that neurites from newborn neurons have to connect with their targets in a very precise way. To accomplish this, there are a number of axonal pathfinding mechanisms to guide the growing axons to their final target. The growing axon, and particularly its most distal

Posterior Commissure Development

At early stages of brain development, the arrangement of a series of longitudinal and commissural axon tracts, which act as an axonal scaffold, is a conserved feature in all vertebrates (Easter et al., 1993, Ware and Schubert, 2011). The presence of such axon tracts may serve as a framework to establish a much more complex wiring, characteristic of the later stages of development. The tract of the posterior commissure (TPC) is part of such early axonal scaffold, together with the ventral

Structure and position in the brain

The SCO is an ependymal differentiation located in the midline roof plate of the caudalmost portion of the diencephalon (prosomere 1), under the PC (Figs. 2.11 and 2.24). Because of the secretory nature of the SCO, it has been regarded as a true brain gland. Concerning its histological structure, two layers of different cell types are present in the SCO: the ependymal and the hypendymal cell layers (Oksche, 1961). The ependymal layer is formed by a tall pseudostratified epithelium in contact

SCO-Spondin as an Axonal Guidance Molecule

The initial studies concerning the SCO–RF complex proposed functions related to the regulation of CSF composition and CSF flow, hydrosaline homeostasis, or some role in development (described in Section 4.6). The posterior description of the molecular features of the SCO secretion steered the attention to a potential participation in axonal guidance, based on the similarities found with other already known molecules displaying this function, and on the evidences obtained from in vitro

Expression of Axonal Guidance Molecules in the Subcommissural Organ

SCO-spondin represents the major compound synthesized by the SCO cells. As discussed previously in this review, it is presumably involved in the formation of the PC. As occurs in the FP, midline structures make use of a wide variety of axonal guidance cues to regulate the crossing of axons. Interestingly, some well-characterized axonal guidance molecules are also expressed by the SCO cells at the time of PC development, so they should be considered as potential regulators of the formation of

Subcommissural Organ-Posterior Commissure Alterations in Mutant Models

During the development of vertebrates, neural cells are produced in the ventricular zone of morphologically defined territories that divide the embryonic neural tube in a series of dorsoventral and caudorostral fields (Puelles and Rubenstein, 1993). Each of these regions is characterized by the expression of specific regulatory genes that control the expression of other regulatory genes, growth factors, cell surface receptors, ECM proteins, cell adhesion molecules, guidance cues, or neural cell

Concluding Remarks

The formation of commissures and decussations in the CNS is a complex process controlled by a plethora of axonal guidance cues. A set of glial and, to a lesser extent, neuronal cell populations located at the midline control their formation. Among them, the SCO, located at the midline of the diencephalic roof, has been associated with the development of the PC. The most remarkable feature of the SCO is its secretion: a giant glycoprotein, the SCO-spondin, belonging to the thrombospondin

Acknowledgments

The authors are grateful to Dr. Guillermo Estivill-Torrus (IMABIS, Málaga, Spain) for the generous gift of images of Pax6 null mutant mice, to Dr. Teresa Caprile (Universidad de Concepción, Chile) for her kindness in sending some original images and for her critical reading of some portions of the chapter, and to Dr. Harvey B. Sarnat (Faculty of Medicine and Alberta Children's Hospital, Calgary, Canada) for helpful information about commissures and decussations. Rick Visser is a member of

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