Subcommissural organ

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Brain: Subcommissural organ
Gray715.png
Mesal aspect of a brain sectioned in the median sagittal plane. (Subcommissural organ not labeled, but region is visible, near the pineal gland.)
Latin organum subcommissurale
NeuroNames hier-474
MeSH Subcommissural+organ
NeuroLex ID birnlex_1028

The subcommissural organ (SCO) is a small ependymal gland of the circumventricular system, located in the dorsocaudal region of the third ventricle, at the entrance of the mesencephalic aqueduct (aqueduct of Sylvius). The SCO is a phylogenetically ancient and conserved structure of the vertebrate phylum. It has its name because of the localization in the brain. The organ's main functions are unknown; nevertheless, some evidences suggest that the organ may participate in different process, such as the clearance of certain compounds and the circulation of the cerebrospinal fluid, and it could also play a role in some morphogenetic mechanisms.[1][2]

History[edit]

In 1860, Reissner, anatomist at the University of Dorpat, published a monograph on the microscopic structure of the spinal cord of Petromyzon fluviatilis. He described a string of 1.5 μm in diameter characterized by its high refringence, its extremely regular shape, and its lying free within the central canal. In 1866, Kutschin confirmed Reissner’s observations and named the fibrous structure Reissner’s fiber.[1][2]

Edinger (1892) described, in sharks, what later was known as “the subcommissural organ”. Studnicka (1900), called attention to uncommonly tall ependymal cells covering the posterior comissure of P. fluviatilis. Sargent, also in 1900, establishes the basis of what is presently regarded as the subcomissural organ – Reissner fiber complex. Finally, in 1910, Dendy and Nicholls introduce the term “subcommissural organ” to describe this brain gland.[1][2]

The rich vascularization of the SCO was first reported by Pesonen (1940). In 1959, Helmut Hofer postulated that this organ, despite its structural and functional differences, is a highly secretory component of the circumventricular system.[1][2]

The subcommissural cells[edit]

The subcommissural cells, specialized in the secretion of glycoproteins, are arranged into two polarized layers: ependyma and hypendyma. The first one (formed by a very high cylindrical cells) release their secretions into the ventricular cerebrospinal fluid and the hypendyma cells (located under the ependyma), characterized by numerous blood capillaries and glial cells, projects into the local blood vessels and to the subarachnoidal space.[1][2]

The ependymal cell bodies present a clear zonation, specially marked in certain species: the perinuclear region - the most distinct ultrastructural feature off virtually all species is the presence of large and dilated cisternae of the rough endoplasmic reticulum (RER); intermediate region – constituted mainly by the RER and the Golgi apparatus (its not certain the involvement of the Golgi apparatus in the secretary process of the subcommissural organ); subapical region – short region, with microtubules, mitochondria and smooth endoplasmic reticulum; and an apical region – projecting a large protusion into the ventricle.[1][2]

The ependymal cells of the SCO, are also involved in the production of brain transthyretin, which is a protein involved in the transport of thyroid hormones in blood and also plays a role in transporting the cerebrospinal fluid.[3] Ependymal cells also secrete high molecular mass glycoproteins into the cerebrospinal fluid in which the bulk of them condense to form a filamentous structure, named Reissner’s fiber.[4]

The subcommissural organ/Reissner’s fiber complex is one of the factors involved in the cerebrospinal fluid reabsorption and circulation, which under normal physiological conditions, is secreted continuously, although this secretion undergoes circadian variations. Together, this complex is associated to functions regarding electrolyte and water balance.[4][5]

One of the proteins, secreted by the subcommissural organ and expressed in the central nervous system, present in the Reissner’s fiber is spondin. Subcommissural organ - spondin is a “giant” (5000 amino acids) glycoprotein (thrombospondin superfamily) found in Vertebrata. This glycoprotein shares molecular domains with axonal pathfinding molecules.[5]

The ependymal cells and the SCO–spondin secretion are suspected to play a role in homeostasis.[6]

Some studies indicate the presence of both tyrosine-hydroxylase-immunoreactive nerve fibers and dopamine receptors in the SCO ependyma.[7]

All brain capillaries of the blood-brain barrier structures have glucose transporters (GLUT1). These transporters are generally absent in leaky barrier structures. The circumventricular organs that are known to have leaky barrier capillaries were stained by fibronectin antibodies but not by GLUT1 antibodies. So, the subcommissural organ appeared to be unique showing neither GLUT1 nor capillary.[8]

The ependymal cells and the subcommissural organ–spondin secretion are suspected to play a role in homeostasis.[6] Ependymal cells also secrete high molecular mass glycoproteins into the cerebrospinal fluid in which the bulk of them condense to form a filamentous structure, named Reissner’s fiber.[4][9]

There is also evidence suggesting that the SCO activity in adult animals may be regulated by serotonin.[10]

Reissner’s fiber[edit]

Reissner’s fiber (RF) is a complex and dynamic structure present in the third and fourth ventricles and in the central canal of the spinal cord, observed in almost all vertebrates, except in humans and anthropoid apes.[11][12]

It is formed by the assembly of complex and variable high weight molecular glycoproteins secreted by the SCO that are released to the cerebrospinal fluid. At least five different proteins were found, of 630 kDa, 480 kDa, 390 kDa, 320 kDa and, the major constituent, 200kDa that is present in both RF and cerebrospinal fluid, CSF. One of the most important RF-glycoproteins secreted by the SCO has been named SCO-spondin and is of major importance especially during embryonic life.[2][13]

Reissner’s fiber grows caudally by the addition of those glycoproteins at its cephalic end and extends along the brain aqueduct (Aqueduct of Sylvius), and the entire length of the central canal of the spinal cord, growing continuously in the caudal direction. It is just a small part of the secretions made by SCO and remains a matter of speculation, probably involved in many physiological functions as clearance of monoamines, detoxification of the CSF, neuronal surviving or the control of water balance.[2][14][15]

The glycoproteins forming RF can be found in three conformations, the first on is when the material aggregates over the SCO cilia, the so-called pre-RF, the second and most studied form known as the proper RF which is a cylindrical regular structure, and finally a third and final form, massa caudalis, known as the final distribution and the final assembly of the proteins.[15]

Formation[edit]

This fiber is essentially made by glycoproteins, secreted by the subcommissural organ, of high molecular mass that are released into the cerebrospinal fluid. Here they aggregate on the top of the cilia, forming a thin film that becomes further packed in a highly ordered fashion to form threadlike supramolecular structure.[2]

The pre-RF material appears in the form of loosely arranged bundles of thin filaments. After this, it is plausible that some biochemical modifications may occur to the pre-RF material in order for it to condensate and form the exact Reissner’s fiber, such as disassembly and passage into neighboring vessels. Some of these changes may decrease the reactivity of the molecules, and this should be considered as a transitory stage, from pre to the proper RF, in which the accessibility of the antibodies to the epitopes is decreased. This lack of immunoreactivity could be due to the spatial distribution of sialic acid residues, with negative charge, within the fiber or might be the result of bound compounds interfering with the accessibility of the antibodies to RF- glycoproteins.[15]

The massa caudalis is the final form of this assembly of proteins, and is mostly related with the distal side of accumulation of the fiber and this final form have more filaments and is less compact than the middle form of the fiber.[2]

The secretory material is first syntethized at embryonic day3 (E3) by morphological undifferentiated neuroepithelial cells. At E7, post- coitum, the SCO-spondin it is released to embryonic CSF (ECSF), however RF does not form until E11 and only at E12 the RF is present in the lumbar spinal cord. The mechanisms that trigger RF formation remain unknown, but probably factors other that ventricular released must be required for the formation of the fiber, like the hydrodynamics of the CSF.[14]

SCO-RF complex[edit]

This complex may participate in the maintenance of water and electrolyte homeostasis (osmoregulation), during ontogeny and in the composition of the cerebrospinal fluid.[14][15]

The SCO-RF has been linked to various and different aspects of water and electrolyte metabolism and it is proven that water deprivation enhances the secretory activity of the SCO. This helps prove the correction between this complex and the adrenal cortex and it has been reported the presence in the SCO-RF of receptors or binding sites for peptides involved in hydromineral balance such as angiotensin II. This complex is involved in many physiological functions like development of spinal cord, the pathophysiology of lordosis or the neuronal survival in a more developmental pathway.[5][16]

RF and the cerebrospinal fluid[edit]

Reissner’s fiber, because of the sialic acid residues with negative charge, might participate in the cleaning of the CSF. The glycoproteins bind biogenic amines present in the CSF like dopamine, serotonin or noradrenaline controlling this way the concentration of these monoamines by ionic change. There are, however, differences in the biding characteristics of each of these amines; the binding of serotonin is more unstable, and it occurs only when its CSF concentration is high, but on the other hand, noradrenaline binds strongly to the RF and remains bound as it moves along the central canal in the same binding site of adrenaline.[5][17]

The concentration of these monoamines in the CSF in Reissner’s fiber deprived animals was investigated, and it was possible to conclude that this fiber is involved in the cleaning of the liquid because those animals display as increased in the CSF concentration of several amines, being L-DOPA the one with the highest rise. All findings obtained indicate that RF binds monoamines present in the ventricular CSF and then transports them along the central canal. In the absence of RF, the CSF concentration of monoamines increased sharply.[18]

SCO-spondin, a glycoprotein of the SCO/RF complex[edit]

The primary structure of the major constituent of bovine RF, SCO-spondin, has been fully established as a large N-glycosylated protein (450 kDa).[19][20] Many lines of evidence denote that SCO-spondin plays a role in CNS development.[21] This molecule belongs to a protein superfamily exhibiting conserved motifs of the thrombospondin type 1 repeat. Proteins of this family are strongly expressed during mammalian CNS development, being involved in mechanisms of cellular adhesion and axonal pathfinding (a process by which neurons send out axons to reach the correct targets during neural development).[21]

Numerous investigations have been directed towards the identification and characterization of the secretory compounds of the SCO, clarifying partially its function. Immunoblot analyses of bovine SCO using antibodies against RF glycoproteins allowed the identification of high molecular weight glycoproteins of 540, 450, 320 and 190 kDa.[21] The 540 and the 320 kDa compounds would correspond to precursor forms.[22]

Multidomain organization[edit]

The main SCO-spondin isoform consists of multiple domains. This multidomain organization is a special feature of the Chordate Phylum, and there is a high degree of conservation in the amino acids composition in mammals.[23] The complete sequence and modular organization of SCO-spondin was first characterized in Bos taurus.[19] The structure of this protein is unique as it presents a mosaic arrangement of these domains along the backbone.

The putative function of SCO-spondin in neuronal differentiation is discussed regarding these features and homologies with other developmental molecules of the central nervous system exhibiting TSR domains, and involved in axonal guidance.[20] Peptides corresponding to SCO-spondin TSR domains strongly increased adhesivity and neuritic outgrouth of cortical neurons and induced disaggregation of spinal cord neurons. Therefore, it is a candidate to interfere with neuronal development and/or axonal guidance during ontogenesis of the central nervous system in the modulation of side-to-side and side-to-substratum interactions, and also in promoting neurite outgrowth.[20]

The identification of conserved domains including Emilin (EMI), von Willebrand factor D (vWD) low-density lipoprotein receptor type A repeats (LDLrA) domains, SCO repeats (SCORs), 26 thrombospondin type 1 repeats (TSRs), a coagulation factor 5/8 type C (FA5-8C) or discoidin motif and a C-terminal cystin knot (CTCK) domain provides a wider insight into the putative function of this protein. Similar types of arrangement was encountered in zonadhesins and immunoglobulin G (IgG) FC binding fragment which may account for SCO-spondin functional aspect on promoting cell-to-substratum adhesivity.[23]

The presence of low-density lipoprotein receptor type A (LDLrA) domains repeated ten times in the consensus sequence could provide a hint as to the function of SCORs, since LDLrA are known to interact with proteases or protease inhibitors.[24] There may be a functional link between LDLrAs and SCORs, which could both be involved in the regulation of either protease activation or protease inhibition.[23] The motifs coagulation factor 5/8 type C or discoidin and thrombospondin type 1 repeat (TSR) present in SCO-spondin consensus were initially described in blood proteins, where they were shown to play a role in coagulation or platelet aggregation. SCO-spondin and F-spondin share a similar pattern of expression in the floor plate, flexural organ and subcommissural organ and could have a redundant activity. The biological function of F-spondin and SCO-spondin on the deflection of commissural axons in the neural tube was assessed respectivelly by experiments of gain and loss of function[25] and by analyses of mutants with defective floor plate. F-spondin and SCO-spondin were both shown to promote neurite outgrowth of various neuronal cell populations, in cell culture.[26]

SCO-spondin may interfere with several biological events during early ontogenetical development of the CNS. Nevertheless, SCO-spondin is also present during the adult life, and similarly to thrombospondins, which act on various biological systems, i.e., neuronal differentiation, angiogenesis and platelet aggregation.[27]

SCO, SCO-spondin and Reissner's fiber during development[edit]

SCO[edit]

Despite being a much conserved structure throughout evolution, there are some differences on the SCO from different mammals. It is the first secretory structure to differentiate and remains fully developed and functional during the life of almost every vertebrate, excluding bats, anthropoid apes and humans. More specifically, in humans, the SCO development has a regressive nature. It reaches its apex development in fetus from 3 to 5 month old, functioning as a fully active secretory structure of the brain during this time span, and extending from the pineal recess over the posterior commissure to the mesocoelic recess. It is composed by a characteristic high columnar epithelium, which is not found in the adult SCO. Following this maxed developed state, the SCO starts regressing and in children from 3 to 4 years old it already has a vestigial character, being reduced to islet like structures on the adult. Although the remaining cells can possess some secretory material the SCO is truly vestigial in both structure and secretory function, in adults.[13]

SCO-spondin[edit]

As part of the embryonic cerebrospinal fluid (eCSF), SCO-spondin is of the uttermost importance in the development of the neuronal system, being a key protein in the balancing of differentiation and proliferation of the neuroepithelium. It starts being secreted by the diencephalic floor plate in the first embryonic stages playing an important part in the development and differentiation of structures such as the pineal gland.[28] In particular, the SCO-spondin appears to have a major role on the growth of the posterior commissure (PC), which was proved when mutants lacking SCO, and hence had no SCO-spondin, where unable to form a functional PC. On early stages of development the axonal growth is stimulated, being inhibited afterwards.[29] A steep gradient of spondin expression in the neuroepithelium signals the need for different processes to take place, favoring the fasciculation on the cephalic region and the incorporation of new neurons on the caudal region. As such, the lower concentrations of SCO-spondin in the caudal region favor the axonal outgrowth and incorporation of new axons on the posterior commissure and the higher concentrations in the cephalic region promotes the interactions between the neighboring axons.[28] In conjugation with the secretion of SCO-spondin, the midline positioning of the SCO assumes a great importance on the axon guidance process. This positioning facilitates the signaling of the turning points for the axons, through the spreading of spondin.[29] In addition to the functions in axon guidance and related growth of the posterior commissure, the SCO-spondin also appears to have a role on the adhesion of the trophoblast to the uterine walls. There is a slightly different SCO-spondin produced in the trophoblast, most likely due to alternative splicing. This spondin may recognize the classic protein on the uterine wall, facilitating the adhesion.[30]

Reissner's fiber[edit]

The Reissner's fiber is also important on the morphogenetic neuronal processes, being involved on neuronal survival, aggregation and neurite extension. In vitro studies demonstrated that the presence of RF, in conjunction with glial cells, is essential to the survival of neuronal cells. The studies seem to point that the RF might bind some of the growth factors produced by glial cells and transport them to the neurons. On the process of neuronal aggregation, RF seems to serve as a control factor in direct cell-to-cell communication, favoring neuronal aggregation when the density of neurons is low and preventing this aggregation when the density gets higher. Although the mechanism behind this is not well understood, it is known to be linked to the different domains in SCO-spondin that are related to coagulation factors and TSRs, as referred above. Furthermore, the RF as a part on the neurite extension, promoting neurite outgrowth from both spinal and cortical neurons, in cell cultures, which may also be connected to the TSR domains of SCO-spondin.[20]

Clinical significance[edit]

Hydrocephalus[edit]

Given that the subcommissural organ is not highly permeable and does not possess fenestrated capillaries like other subventricular organs, it has emerged as a major site of congenital hydrocephalus.[31][32] It is suggested that this is related to immunological blockage of SCO secretions and Sylvian's aqueduct malformation[33] and obliteration or turbulent cerebrospinal fluid flow due to the absence of Reissner's fibers.[21] There is evidence that in transgenic mice the overexpression of Sox3 in the dorsal midline of the diencephalon in a dose-dependent manner[34] and that the conditional inactivation of presenilin-1[35] or the lack of huntingtin[36] in wnt cell lineages leads to congenital hydrocephalus, which highlights the role of these proteins mediating the relation between the SCO and the condition. A more recent study using HTx rats reinforced the idea that the abnormal and dysfunction of the SCO precedes the development of the hydrocephalus.[4]

Other pathologies[edit]

It is reported that in spontaneously hypertensive rats there is a relation between SCO and hypertension due to changing in its secretor activity and protein composition.[37][38]

References[edit]

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