SCO-Spondin is a large protein that exists in most chordates and is encoded in humans by the SSPOgene.[5] Sco-Spondin is a glycoprotein which is 550 amino acids long or about 60.5 kDa. SCO-Spondin is a matricellular protein, secreted by the Subcommissural organ (SCO) located beneath the posterior commissure located at the entrance of the Sylvian aqueduct,[6][7] into the cebereal spinal fluid (CSF) The SCO is made up of both ependymal cells and hypedymal cells.[6] This protein is made in endoplasmic reticulum inside of the SCO. This structure is created very early in development, and begins secreting SCO-Spondin very early in vitro. In this Sco-spondin appears to be a mix between a matricellular protein and has the binding features of an LDL-binding ligand. Given this it is shown that SCO-spondin has the same abilities as other similar shaped proteins enabling it to bind to other CSF molecules. The different domains found on this protein and the LDL binding show its ability to interact with many different CSF molecules in different conditions. It has also been shown to be a key factor in the development of Reissner fibers (RF). When looking at SCO-spondin it is important to note how large this protein is and to see how many binding domains it contains[8] which can influence how and what it is able to bind to. With so many domains it is able to preform many functions many of which are not discovered yet are continued to be researched. SCO-Spondin is also found cephalochordates and urochordates and is made in a different organ called the infundublar organ on the rostral floor plate. The function is majorly the same as well as the processes of when it is secreted as well as how the protein works.
There are many current projects and much research being done currently to determine what exactly SCO-Spondin is responsible for. Though many purposes of this protein have come out there is much to learn. Currently there is research done in Zebra fish, mouse,[9] and birds,[10] each one of these projects continues to show the similarities of the protein in each creature. Along with furthering our understanding of SCO-Spondin. There is much disorder to the structure of SCO-spondin. This protein is also very hard to find in the human adult so much of its function there is largely unknown however several key functions have been found in studies with other creatures.
Functions
While not exactly known early testing is shown that SCO-Spondin plays a part in commisural axon growth and formations of Reissner's Fibers (RF). This is a large fibrous network essential in all chordates and is created by the SCO-Spondin. How it works is the SCO secretes the Sco-spondin, this large molecule is now in the CSF which it then aggregates and forms a film along the hindbrain floorplate where it can then build upon itself. It then extends the length of the spinal cord and 4th ventricle of the brain. It is important to note that these proteins are in constant movement getting replaced and moved along the chain.[8] These SCO-spondin that are used in the Reissner's Fibers growth are eventually disaggregated at various speeds depending on the animal. This RF acts as a 'conveyor belt' of SCO-spondin which can transport nutrients waste among other things. The SCO-spondin is very suitable for this job with the 80+ binding sites many which preform different tasks and have many different structures. Though the RF is different in every creature, it is maintained that it is made of bundles of filament that are 2-5μm which are then assembled into 10 nm thick which runs along the length of the entire RF. These bundles that run the length are the structure of the RF which are essential to maintaining its integrity.
Early in development SCO-spondin shows a different function, modulation.[8] With this it is seen that SCO-Spondin has an effect on the neurodifferention of the neuroepithelium in vivo. The secretion of SCO-spondin varies per animal, it can happen from hours to weeks after the animals creation in vitro. The secretion of SCO-sponding influences the rate of RF growth with aquatic chordates forming much earlier than mammal or avian RF where it is delayed, theorized to be because of their aquatic nature.
As well as previously stated there is also evidence that SCO-spondin acts as a concentration regulator while on the RF moving the concentration of molecules along the RF chain. Due to this it can be said that SCO-Spondin plays a part in maintaining the organisms homeostasis inside the CSF, by binding to different molecules controlling their concentration and release into the CSF.
In one study[8] with Zebra fish showed a disruption of cysteine at the LDL domain via hypomorphic missense mutation can disrupt the secretion of SCO-spondin while also dissembling the RF. This same study also cites two EGF-like domains which can help regulate neuron self renewal. This study also highlighted the importance of SCO-spondin in keeping neuronal cells alive, by binding to the apical membrane of nueroepitheial cells. The zebrafish that had a malformed SCO-spondin or missing it entirely had a high mortality rate and high rate of brain malformation. In this same study, the Zebra fish who had their SCO-spondin inhibited in their SCO failed to live, the RF could not form correctly and became curved. Along with this the Zebra Fish had severe brain malformations which caused it pass away. In another study[11] done with Zebra fish the lack of sco-spondin was linked to scoliosis inside of zebra fish, though not fatal, the condition continued to worsen. In this study two recessive alleles were discovered to have caused this, along with different aspects of the rest of the gene. This scoliosis would continue through live and these fish would not be viable as fully grown fish.
Due to the fact that human SCO-Spondin is not well researched it is not completely known what role it plays in the adult human.[7] It has been observed in the fetal and infancy stages of humans.[8]
Domains and Structure
As stated SCO-Spondin is a large molecule which gives researchers reason to believe that it has many different purposes in the body.[8] With many different domains that can inhibit, bind, regulate, and maintain homeostasis. There are many functions of this protein. The matricellular domains of SCO-spondin are, TSR, vWF-C, EGF-like, and CTCK.
TSR Domain
This domain is found in many matricelluar proteins, its function is cell attachment, protein to protein interactions and protein glycoaminoglycan interactions.[8] There are many molecules that can interact with this domain some include FGF-2,[8] and extracellular molecules. Specifically in SCO-spondin there are 27 TSR domains. Some uses of this domain would include a regulatory use as FGF-2 is present in the CSF, which would mean that SCO-Spondin and FGF-2 would have to interact.
vWF-C Domain
The vWF-C domain is a 'chordin like cysteine rich repeat', which plays a role in regulating TGF-β and BMPs.[8] Due to the fact that these two proteins are present in the CSF this would highly suggest that there would be interaction with the 7 SCO-spondin vWF-C domains. Though the exact function is not known due to the nature of these domains it would suggest that they play a role in transporting and the concentration of the TGF-β1,2 and these BMPs.
CTCK Domain
CTCK ( Cysteine Knot C terminal domain) is defined as 6 cysteine amino acids, with 3 intertwined disulfide bridges. This domain is found on many other thing such as hormones, mucins, cytokines and vWF-C. This domain is responsible for cell to adhesion[12] and dimerization and polyermization for the formation of long polymers. In SCO-Spondin's case this points in the direction of assistance of polyermization during the formation of RF and a nerve growth factor for the body.
EGF-Like
The EGF-like domain follows a structure like other ligand binding domains, 7 LDLrA domains followed by 2 EGF-like domains. The LDL portion of this domain is responsible for being a receptor.[13]The molecules that can be bound to this receptor are extensive, from apolipoproteins to amyloid-β[8] In this case with SCO-Spondin the purpose of this domain is to bind to the similar molecules that the LDL family of proteins bind to. In the womb SCO-spondin plays a large role in how the RF develops and the nuerodifferention process making domain very important to maintaining correct brain development during this period.[11] Next the EGF-like portion of this large LDL domain is able to bind to many different extracellular receptors. Found on many other proteins such as tenascin and TSP, it resposnble for different things in both though both preform binding roles. Due to the shape and amount of EGF-like domains it is able to bind to FGF-2[14] in the CSF. Allowing it to preform regulation of neural stem cell self renewal and regulation.
Along with all these domains there are many different others that are related to SCO-spondins other functions such as the forming of the Reissners Fibers' that SCO-spondin forms. In this process it is the polymerization of SCO-spondin, the domains associated with this are the EMI, vWF-D and TIL ( Trypsin inhibitor like cysteine rich) domains.
EMI
This domain is made of 6-7 cysteine residues, which are present in some other proteins as well. This is likely responsible for intramolecular disulfide bridges and multimer formation.[15][8] This would mean that this domain helps form the RF with building the connections between the SCO-Spondin.
vWF-D
This domain is a very large domain that is found in a few other proteins,[8] and is suggested that it has a function to help the polymerization process of SCO-spondin. Along with this it has a self organization process in which it can form long flexible polymers. Helping to point how the RF is formed from SCO-spondin.
TIL
The TIL domain was previously classified as SCO-spondin repeats but has been since reclassified as its own domain[16]responsible for mianting SCO-spondin structural integrity. SCO-spondin contains 16 TIL domains, 3 each of which is placed after a vWF-D domain previously described.
There are few regulators to SCO-spondin inside the body, in a study with zebrafish,[17] the voltage gated channel Kv2.1 can regulate the assembly of SCO-spondin and regulate when it can bundle into the Reissner fibers. Kv2.1 plays a role in channels inside the body, whether it be cholesterol lipid rafts and plasma membrane potential. It was shown that a change to the Kv2.1 can directly impact the rate of SCO-spondin being made. Along with this it was theorized and lightly linked to cholesterol as when cholesterol production was blocked, the SCO-spondin was being produced however the RF failed to form completely. However this is only in complete cholesterol depravation, in cases where acute cholesterol deficiencies are in play, the Kv2.1 channel can compensate and produce more SCO-spondin.
History
SCO-Spondin was first discovered in 1996[5] and then was later sequenced in 2000. When discovered it was labeled as a member of the thrombospondin[5] family. Sharing similar structures to other proteins of this family helps complete our understanding of this molecule. However the SCO is thought to be an ancient brain organ. First discovered in the 1900s[18] its function was not known for a very long time, though very early on in its discovery was connected to the RF. A full description of the organ came in the 1970s[19] in rats with different light and scanning electron microscopy. Which then leads to the SCO-spondins discovery in 1996. Currently though in humans the gene that codes for SCO-spondin, SSPO or SSPOP, is classifed as a pseugene, which means that it resembles a gene but currently cannot code for a working protein. However irregular SCO-spondin has been novely linked to several health disorders such Parkinson's among other diseases. Ongoing research is presently going on and studies published as recently as 2023[20] are continuing our understanding of this protein, which aim to unravel the mysteries around this elusive protein inside humans and all other vertebrates.
↑"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
123Gobron S, Monnerie H, Meiniel R, Creveaux I, Lehmann W, Lamalle D, etal. (May 1996). "SCO-spondin: a new member of the thrombospondin family secreted by the subcommissural organ is a candidate in the modulation of neuronal aggregation". Journal of Cell Science. 109 (5): 1053–1061. doi:10.1242/jcs.109.5.1053. PMID8743952.
12Meiniel A (March 2001). "SCO-spondin, a glycoprotein of the subcommissural organ/Reissner's fiber complex: evidence of a potent activity on neuronal development in primary cell cultures". Microscopy Research and Technique (in German). 52 (5): 484–495. doi:10.1002/1097-0029(20010301)52:5<484::AID-JEMT1034>3.0.CO;2-0. PMID11241859.
↑Schoebitz K, Garrido O, Heinrichs M, Speer L, Rodríguez EM (1986-01-01). "Ontogenetical development of the chick and duck subcommissural organ. An immunocytochemical study". Histochemistry. 84 (1): 31–40. doi:10.1007/BF00493417. PMID2420757.
12Troutwine BR, Gontarz P, Konjikusic MJ, Minowa R, Monstad-Rios A, Sepich DS, etal. (June 2020). "The Reissner Fiber Is Highly Dynamic In Vivo and Controls Morphogenesis of the Spine". Current Biology. 30 (12): 2353–2362.e3. Bibcode:2020CBio...30E2353T. doi:10.1016/j.cub.2020.04.015. PMID32386529.
↑McDonald NQ, Hendrickson WA (May 1993). "A structural superfamily of growth factors containing a cystine knot motif". Cell. 73 (3): 421–424. doi:10.1016/0092-8674(93)90127-c. PMID8490958.
↑Margosio B, Rusnati M, Bonezzi K, Cordes BL, Annis DS, Urbinati C, etal. (2008-01-01). "Fibroblast growth factor-2 binding to the thrombospondin-1 type III repeats, a novel antiangiogenic domain". The International Journal of Biochemistry & Cell Biology. 40 (4): 700–709. doi:10.1016/j.biocel.2007.10.002. PMID17996481.
↑Doliana R, Bot S, Bonaldo P, Colombatti A (November 2000). "EMI, a novel cysteine-rich domain of EMILINs and other extracellular proteins, interacts with the gC1q domains and participates in multimerization". FEBS Letters. 484 (2): 164–168. Bibcode:2000FEBSL.484..164D. doi:10.1016/S0014-5793(00)02140-2. PMID11068053.
↑Meiniel O, Meiniel A (February 2007). "The complex multidomain organization of SCO-spondin protein is highly conserved in mammals". Brain Research Reviews. 53 (2): 321–327. doi:10.1016/j.brainresrev.2006.09.007. PMID17126404.
↑Dendy A, Nicholls GE (1910). "On the Occurrence of a Mesocoelic Recess in the Human Brain, and Its Relation to the Sub-Commissural Organ of Lower Vertebrates; with Special Reference to the Distribution of Reissner's Fibre in the Vertebrate Series and Its Possible Function". Proceedings of the Royal Society of London. Series B, Containing Papers of a Biological Character. 82 (558): 515–529. doi:10.1098/rspb.1910.0046. ISSN0950-1193. JSTOR80262.
Meiniel A, Meiniel R, Gonçalves-Mendes N, Creveaux I, Didier R, Dastugue B (2004). The Thrombospondin Type 1 Repeat (TSR) and Neuronal Differentiation: Roles of SCO-Spondin Oligopeptides on Neuronal Cell Types and Cell Lines∗. International Review of Cytology. Vol.230. pp.1–39. doi:10.1016/S0074-7696(03)30001-4. ISBN978-0-12-364634-7. PMID14692680.
Gonçalves-Mendes N, Simon-Chazottes D, Creveaux I, Meiniel A, Guénet JL, Meiniel R (July 2003). "Mouse SCO-spondin, a gene of the thrombospondin type 1 repeat (TSR) superfamily expressed in the brain". Gene. 312: 263–270. doi:10.1016/S0378-1119(03)00622-X. PMID12909363.
Gonçalves-Mendes N, Blanchon L, Meiniel A, Dastugue B, Sapin V (May 2004). "Placental expression of SCO-spondin during mouse and human development". Gene Expression Patterns. 4 (3): 309–314. doi:10.1016/j.modgep.2003.10.004. PMID15053980.
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