Oncomodulin

Last updated

Oncomodulin is a parvalbumin-family calcium-binding protein expressed and secreted by macrophages (that typically traffic to tissue as an inflammatory response or after injury). [1]

Contents

Oncomodulin is present in the eye. [2] It is small, acidic, has a high calcium-binding activity, and consists of 108 amino acid residues. [3] It is released by macrophages in the vitreous and the retina to promote nerve regeneration in the eye. [2] This regeneration can be done in response to inflammation in the eye and promote regrowth in the eye to repair retinal injury. The regeneration effects of oncomodulin outcompetes other neurotrophic factors like BDNF, CNTF, and GDNF. [2] When added to retinal nerve cells in a petri dish with no other growth factors present, oncomodulin has been shown to promote neuron regrowth at 5-7 times the normal rate. [4]

Oncomodulin has been found in cytotrophoblasts of human and rat placenta and in the early stages of embryos. [3] In vivo, oncomodulin promotes regeneration of the optic nerve in rats. [5] It has also been found in different types of human and rodent tumors. [3] However, it has never been found in healthy human or rat tissues. [3]

To date, it has been found in the central nervous system in inner ear hair cells and retinal ganglion cells. Oncomodulin promotes axon regeneration in retinal ganglion cells [1] and maintains functioning in mouse cochlear hair cells. [6]

Structure

Oncomodulin is highly conserved across vertebrate evolution (NCBI database). It is a smaller calcium-binding protein (11.7-kDa) which resembles the EF-hand domain of calmodulin (32% sequence identity), alpha-parvalbumin (54%), S100-beta (34%), and calbindin (25%) and resembles alpha-parvalbumin in its N-terminal region (52%). It has a 40-residue N-terminal domain with an inactive calcium binding site and a 70-residue EF-hand domain with one low affinity Ca2+ and Mg2+ binding site and one high-affinity Ca2+ site. [1]

Oncomodulin has a crystal structure and is a 12,000 Mr protein. [7] Two Ca2+ atoms in oncomodulin are co-ordinated with seven oxygen atoms and one water molecule. The third Ca2+ atom is co-ordinated with five oxygen atoms and two water molecules. [7] Both of the Ca2+ molecules are bound to the CD and EF loops. The distances between Ca and O in the molecular structure range from 2.07 A to 2.64 A, which indicates that the molecule is tightly bound together. [7] The backbone structure of oncomodulin closely resembles parvalbumin. [7] It has a 50% amino acid identity to parvalbumin. [3]

Mechanism of Action

For oncomodulin to work properly, it must have elevated levels of cAMP and the sugar mannose, which is present in the vitreous of the eye. [2] cAMP increases the effectiveness of oncomodulin several times more than just having oncomodulin and cAMP alone. [2] Oncomodulin is activated by activating downstream signaling of Ca2+, calmodulin kinase, and gene transcription. [5]

Oncomodulin mRNA production peaks within a day of an inflammatory response. [8] During inflammation, macrophages are released into the eye in order to promote axon regeneration. [9] Inducing an inflammatory response enables the ability of sensory neurons to regenerate their axons through the dorsal roots. [8] The secretion of oncomodulin from macrophages stimulates the growth of neurons. [8] The identity of the receptor for oncomodulin that allows axon regeneration is unknown. [2] It is also unknown whether oncomodulin promotes regeneration elsewhere in the immune system. Signaling complexes that may be important to work with oncomodulin include PI 3 Kinase, MAP Kinase, JAK/STAT, and CaM Kinase II. [2] The depletion of oncomodulin from media in which macrophages grow removes the axon-promoting activity of the media. [5]

Neutrophils are also an important component of oncomodulin activation. Without neutrophils present, macrophages are less effective at stimulating extensive regeneration of neurons. [8] This is because neutrophils enter the area of inflammation before macrophages do. In addition to macrophages, neutrophils are also a major source of oncomodulin production. [8]

In rats, the gene that encodes oncomodulin is under control of a solo oncomodulin LTR that comes from an endogenous intracisternal A-particle. [3] The oncomodulin LTR is only present in rats. Oncomodulin levels are highest in the rat out of all other species that have been previously investigated. [3]

Uses

Oncomodulin plays a key role in patients with eye injuries. It is thought that it can reverse eye damage caused from glaucoma. [4] Oncomodulin is also thought to switch on a variety of genes that are associated with axon regrowth. [4] Eye drops with oncomodulin can be a useful method of promoting nerve regrowth in mild cases of optic gliomas. [4] Oncomodulin has also been seen to stimulate outgrowth from peripheral sensory neurons. [5]

Injections with zymosan can promote macrophages to enter the eye and secrete oncomodulin. [10] This is an effective method of treatment in patients with minor eye damage. [10] Injections into patients with severed spinal cords has shown to restore partial motor function. [2]

See also

Related Research Articles

<span class="mw-page-title-main">Myelin</span> Fatty substance that surrounds nerve cell axons to insulate them and increase transmission speed

In most vertebrates, myelin is a lipid-rich material that surrounds nerve cell axons to insulate them and increase the rate at which electrical impulses are passed along the axon. The myelinated axon can be likened to an electrical wire with insulating material (myelin) around it. However, unlike the plastic covering on an electrical wire, myelin does not form a single long sheath over the entire length of the axon. Rather, myelin sheaths the nerve in segments: in general, each axon is encased with multiple long myelinated sections with short gaps in between called nodes of Ranvier.

<span class="mw-page-title-main">Retina</span> Part of the eye

The retina is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then processes that image within the retina and sends nerve impulses along the optic nerve to the visual cortex to create visual perception. The retina serves a function which is in many ways analogous to that of the film or image sensor in a camera.

<span class="mw-page-title-main">Optic chiasm</span> Part of the brain where the optic nerves cross

In neuroanatomy, the optic chiasm, or optic chiasma, is the part of the brain where the optic nerves cross. It is located at the bottom of the brain immediately inferior to the hypothalamus. The optic chiasm is found in all vertebrates, although in cyclostomes, it is located within the brain.

<span class="mw-page-title-main">Optic nerve</span> Second cranial nerve, which connects the eyes to the brain

In neuroanatomy, the optic nerve, also known as the second cranial nerve, cranial nerve II, or simply CN II, is a paired cranial nerve that transmits visual information from the retina to the brain. In humans, the optic nerve is derived from optic stalks during the seventh week of development and is composed of retinal ganglion cell axons and glial cells; it extends from the optic disc to the optic chiasma and continues as the optic tract to the lateral geniculate nucleus, pretectal nuclei, and superior colliculus.

<span class="mw-page-title-main">Photoreceptor cell</span> Type of neuroepithelial cell

A photoreceptor cell is a specialized type of neuroepithelial cell found in the retina that is capable of visual phototransduction. The great biological importance of photoreceptors is that they convert light into signals that can stimulate biological processes. To be more specific, photoreceptor proteins in the cell absorb photons, triggering a change in the cell's membrane potential.

<span class="mw-page-title-main">Retinal ganglion cell</span> Type of cell within the eye

A retinal ganglion cell (RGC) is a type of neuron located near the inner surface of the retina of the eye. It receives visual information from photoreceptors via two intermediate neuron types: bipolar cells and retina amacrine cells. Retina amacrine cells, particularly narrow field cells, are important for creating functional subunits within the ganglion cell layer and making it so that ganglion cells can observe a small dot moving a small distance. Retinal ganglion cells collectively transmit image-forming and non-image forming visual information from the retina in the form of action potential to several regions in the thalamus, hypothalamus, and mesencephalon, or midbrain.

<span class="mw-page-title-main">Optic disc</span> Optic nerve head, the point of exit for ganglion cell axons leaving the eye

The optic disc or optic nerve head is the point of exit for ganglion cell axons leaving the eye. Because there are no rods or cones overlying the optic disc, it corresponds to a small blind spot in each eye.

<span class="mw-page-title-main">Peripherin</span> Protein-coding gene in the species Homo sapiens

Peripherin is a type III intermediate filament protein expressed mainly in neurons of the peripheral nervous system. It is also found in neurons of the central nervous system that have projections toward peripheral structures, such as spinal motor neurons. Its size, structure, and sequence/location of protein motifs is similar to other type III intermediate filament proteins such as desmin, vimentin and glial fibrillary acidic protein. Like these proteins, peripherin can self-assemble to form homopolymeric filamentous networks, but it can also heteropolymerize with neurofilaments in several neuronal types. This protein in humans is encoded by the PRPH gene. Peripherin is thought to play a role in neurite elongation during development and axonal regeneration after injury, but its exact function is unknown. It is also associated with some of the major neuropathologies that characterize amyotropic lateral sclerosis (ALS), but despite extensive research into how neurofilaments and peripherin contribute to ALS, their role in this disease is still unidentified.

In cellular neuroscience, an axotomy is the cutting or otherwise severing of an axon. This type of denervation is often used in experimental studies on neuronal physiology and neuronal death or survival as a method to better understand nervous system diseases.

<span class="mw-page-title-main">Retinotopy</span> Mapping of visual input from the retina to neurons

Retinotopy is the mapping of visual input from the retina to neurons, particularly those neurons within the visual stream. For clarity, 'retinotopy' can be replaced with 'retinal mapping', and 'retinotopic' with 'retinally mapped'.

Gliosis is a nonspecific reactive change of glial cells in response to damage to the central nervous system (CNS). In most cases, gliosis involves the proliferation or hypertrophy of several different types of glial cells, including astrocytes, microglia, and oligodendrocytes. In its most extreme form, the proliferation associated with gliosis leads to the formation of a glial scar.

Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and differentiation of both developing and mature neurons. Most NTFs exert their trophic effects on neurons by signaling through tyrosine kinases, usually a receptor tyrosine kinase. In the mature nervous system, they promote neuronal survival, induce synaptic plasticity, and modulate the formation of long-term memories. Neurotrophic factors also promote the initial growth and development of neurons in the central nervous system and peripheral nervous system, and they are capable of regrowing damaged neurons in test tubes and animal models. Some neurotrophic factors are also released by the target tissue in order to guide the growth of developing axons. Most neurotrophic factors belong to one of three families: (1) neurotrophins, (2) glial cell-line derived neurotrophic factor family ligands (GFLs), and (3) neuropoietic cytokines. Each family has its own distinct cell signaling mechanisms, although the cellular responses elicited often do overlap.

Optic neuropathy is damage to the optic nerve from any cause. The optic nerve is a bundle of millions of fibers in the retina that sends visual signals to the brain. [1].

<span class="mw-page-title-main">Retinohypothalamic tract</span> Neural pathway involved with circadian rhythms

In neuroanatomy, the retinohypothalamic tract (RHT) is a photic neural input pathway involved in the circadian rhythms of mammals. The origin of the retinohypothalamic tract is the intrinsically photosensitive retinal ganglion cells (ipRGC), which contain the photopigment melanopsin. The axons of the ipRGCs belonging to the retinohypothalamic tract project directly, monosynaptically, to the suprachiasmatic nuclei (SCN) via the optic nerve and the optic chiasm. The suprachiasmatic nuclei receive and interpret information on environmental light, dark and day length, important in the entrainment of the "body clock". They can coordinate peripheral "clocks" and direct the pineal gland to secrete the hormone melatonin.

<span class="mw-page-title-main">Nerve injury</span> Damage to nervous tissue

Nerve injury is an injury to nervous tissue. There is no single classification system that can describe all the many variations of nerve injuries. In 1941, Seddon introduced a classification of nerve injuries based on three main types of nerve fiber injury and whether there is continuity of the nerve. Usually, however, peripheral nerve injuries are classified in five stages, based on the extent of damage to both the nerve and the surrounding connective tissue, since supporting glial cells may be involved.

<span class="mw-page-title-main">S100A9</span> Protein-coding gene in the species Homo sapiens

S100 calcium-binding protein A9 (S100A9) also known as migration inhibitory factor-related protein 14 (MRP14) or calgranulin B is a protein that in humans is encoded by the S100A9 gene.

<span class="mw-page-title-main">LINGO1</span> Protein-coding gene in the species Homo sapiens

Leucine rich repeat and Immunoglobin-like domain-containing protein 1 also known as LINGO-1 is a protein which is encoded by the LINGO1 gene in humans. It belongs to the family of leucine-rich repeat proteins which are known for playing key roles in the biology of the central nervous system. LINGO-1 is a functional component of the Nogo receptor also known as the reticulon 4 receptor.

<span class="mw-page-title-main">Midget cell</span>

A midget cell is one type of retinal ganglion cell (RGC). Midget cells originate in the ganglion cell layer of the retina, and project to the parvocellular layers of the lateral geniculate nucleus (LGN). The axons of midget cells travel through the optic nerve and optic tract, ultimately synapsing with parvocellular cells in the LGN. These cells are known as midget retinal ganglion cells due to the small sizes of their dendritic trees and cell bodies. About 80% of RGCs are midget cells. They receive inputs from relatively few rods and cones. In many cases, they are connected to midget bipolar cells, which are linked to one cone each.

Erythropoietin in neuroprotection is the use of the glycoprotein erythropoietin (Epo) for neuroprotection. Epo controls erythropoiesis, or red blood cell production.

Immune system contribution to regeneration of tissues generally involves specific cellular components, transcription of a wide variety of genes, morphogenesis, epithelia renewal and proliferation of damaged cell types. However, current knowledge reveals more and more studies about immune system influence that cannot be omitted. As the immune system exhibits inhibitory or inflammatory functions during regeneration, the therapies are focused on either stopping these processes or control the immune cells setting in a regenerative way, suggesting that interplay between damaged tissue and immune system response must be well-balanced. Recent studies provide evidence that immune components are required not only after body injury but also in homeostasis or senescent cells replacement.

References

  1. 1 2 3 Yin; et al. (June 2006). "Oncomodulin is a macrophage-derived signal for axon regeneration in retinal ganglion cells". Nature Neuroscience. 9 (6): 843–852. doi:10.1038/nn1701. PMID   16699509. S2CID   9628578.
  2. 1 2 3 4 5 6 7 8 R&D Systems. 2015. Oncomodulin: The Inflammatory Response and nerve regeneration. Accessed from https://www.rndsystems.com/resources/articles/oncomodulin-inflammatory-response-and-nerve-regeneration
  3. 1 2 3 4 5 6 7 Staubli, F.; Klein, A.; Rentsch, J. M.; Hameister, H.; Berchtold, M. W. (November 1995). "Structure and chromosomal localization of the mouse oncomodulin gene". Mammalian Genome. 6 (11): 769–777. doi:10.1007/BF00539001. PMID   8597631. S2CID   11975764.
  4. 1 2 3 4 Grossman, Marc. 2015. Optic Glioma/ Optic Nerve & Growth Factor Eye Drops. Natural Eye Care. Accessed from http://www.naturaleyecare.com/blog/optic-glioma-may-respond-to-nerve-growth-factor-eye-drops/
  5. 1 2 3 4 Yin, Yuqin; Henzl, Michael T.; Lorber, Barbara; Nakazawa, Toru; Thomas, Tommy T.; Jiang, Fan; Langer, Robert; Benowitz, Larry I. (June 2006). "Oncomodulin is a macrophage-derived signal for axon regeneration in retinal ganglion cells". Nature Neuroscience. 9 (6): 843–852. doi:10.1038/nn1701. PMID   16699509. S2CID   9628578.
  6. Tong; et al. (February 2016). "Oncomodulin, an EF-Hand Ca2+ Buffer, Is Critical for Maintaining Cochlear Function in Mice". Journal of Neuroscience. 36 (5): 1631–1635. doi:10.1523/JNEUROSCI.3311-15.2016. PMC   4737773 . PMID   26843644.
  7. 1 2 3 4 Ahmed, FR; Przybylska, M; Rose, DR; Birnbaum, GI; Pippy, ME; MacManus, JP (1990). "Structure of oncomodulin refined at 1.85 A resolution. An example of extensive molecular aggregation via Ca2+". J. Mol. Biol. 216 (1): 127–40. doi:10.1016/S0022-2836(05)80065-8. PMID   2231727.
  8. 1 2 3 4 5 Kurimoto, Takuji; Yin, Yuqin; Habboub, Ghaith; Gilbert, Hui-Ya; Li, Yiqing; Nakao, Shintaro; Hafezi-Moghadam, Ali; Benowitz, Larry I. (11 September 2013). "Neutrophils Express Oncomodulin and Promote Optic Nerve Regeneration". Journal of Neuroscience. 33 (37): 14816–14824. doi: 10.1523/JNEUROSCI.5511-12.2013 . PMC   3771038 . PMID   24027282.
  9. Benowitz, Lary. 2008. Lab Reports Progress in Optic Nerve Regeneration. Glaucoma Research Foundation. Accessed from http://www.glaucoma.org/research/update-on-optic-nerve-regeneration.php
  10. 1 2 Yin, Yuqin; Cui, Qi; Gilbert, Hui-ya; Yang, Yang; Yang, Zhiyong; Berlinicke, Cynthia; Li, Zhiwei; Zaverucha-do-Valle, Camila; He, Huamei; Petkova, Victoria; Zack, Donald J.; Benowitz, Larry I. (17 November 2009). "Oncomodulin links inflammation to optic nerve regeneration". Proceedings of the National Academy of Sciences. 106 (46): 19587–19592. Bibcode:2009PNAS..10619587Y. doi: 10.1073/pnas.0907085106 . PMC   2780793 . PMID   19875691.