Role of cell adhesions in neural development

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Cellular adhesions can be defined as proteins or protein aggregates that form mechanical and chemical linkages between the intracellular and extracellular space. Adhesions serve several critical processes including cell migration, signal transduction, tissue development and repair. Due to this functionality, adhesions and adhesion molecules have been a topic of study within the scientific community. Specifically, it has been found that adhesions are involved in tissue development, plasticity, and memory formation within the central nervous system (CNS), and may prove vital in the generation of CNS-specific therapeutics.

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Image courtesy of Wikipedia user JWSchmidt under the GNU Free Documentation License Adhesion diagram.jpg
Image courtesy of Wikipedia user JWSchmidt under the GNU Free Documentation License

Adhesion classifications

Adhesion ClassificationApproximate Size
Nascent0.25 μm
Focal Complex0.5 μm
Focal Adhesion1-5 μm
Fibrillar Adhesion>5 μm

Adhesions role in cell migration

During early development, cell migration plays a crucial role in neuronal tissue organization. Although still largely under investigation, networks of highly ordered neurons are known to be a vital component of the nervous systems communication with the body. A major mechanism of cellular migration is the translation of internal force, to the external environment. Force transmission can occur through a variety of mechanisms, though adhesion complexes between cell-cell and cell-extracellular matrix (ECM) are a known to be chief mechanisms of this activity. [2] Cell migration is generally classified with four cell processes:

  1. Leading edge protrusion
  2. Adhesion formation
  3. Cell body translation
  4. Trailing edge adhesion detachment

The coordination of these processes allows for the efficient migration of cells through their environment.

Cadherin dependent migration

Scaffold cell-dependent migration, in which neuronal cadherin (N-cadherin) adhesive molecules are tightly regulated, provides one mode of motility in developing neuron tissue. During cell migration, N-cadherin binds the neuron to a glial fiber, and allows for transfer of force, generated by an intracellular actin network treadmilling, to the glial fiber. Force transmission across the cell-glial fiber interface sums over many individual N-cadherin/glial-fiber interactions, allowing required levels of traction force essential for migration. It has also been shown that these adhesive cadherin molecules are internalized, and recycled by the migratory neuron. This cadherin recycling mechanism is thought to be substantial in the neural adhesion-based migratory pathway. [3] Cadherin based migration is essential to tissue organization in the central nervous system, specifically in cortical layer formation.

It has also been suggested that the N-cadherin pathway may be crucial in neuron differentiation, as knockdown of the N-cadherin pathway leads to premature neuron differentiation.

Integrin dependent migration

Integrin dependent cell migration can be described as protein plaques that form the mechanical linkage between the intracellular and extracellular environments. One major components of this classification of cell migration, integrin, is a trans-membrenal protein dimer, which binds ECM components on its external domains and actin cytoskeletal components on its intra-cellular domains. These adhesions couple forces between the intracellular and extracellular space through both actin retrograde flow mechanisms (which have been described as a molecular clutch), and through actin-myosin protein contraction machinery. It is thought that these adhesions are involved in mechanosensing, that is, they respond both physically and chemically when exposed to various physical environments. [4]

Growth cone extensions

Growth cones function as structural and chemically sensitive axon-directing cellular organelles. Growth cones are highly dynamic in nature and contain a dynamic actin cytoskeleton in their peripheral region undergoing a constant retrograde flow. This retrograde force provides a mechanism for the growth cone to respond to direction cue, thereby directing neuronal axons. Growth cones are known to respond to various mechanical cues, which may be vital in proper nervous system development as growth cones experience a wide variety of mechanical environments as they navigate the extracellular space. Research suggests that growth cones from different regions of the brain may respond to mechanical cues differently. It has been demonstrated that neural cells located in the hippocampus aren't sensitive to varying mechanical stiffness as it related to outgrowth, where cells originating from the dorsal root ganglion show maximal outgrowth on surfaces of approximately 1 kPa. Both hippocampal and dorsal root ganglion neural growth cones show increased traction force generation on increased stiffness substrates. [5] Growth cones utilize integrin migratory machinery such as integrins, but are not a class of cell migration.

Thy-1 adhesion protein

Thy-1 (or CD90.2) is a membrane bound glycoprotein that has been shown to be involved in the axon guidance pathway. This protein has been shown to be highly mobile, as it contains a GPI membrane anchor. Although much of the details are elusive, it is known that thy-1 interacts with the protein dimer integrin found on astrocytes, forming aggregates that can inhibit neurite outgrowth and extension. Thy-1 has also been shown to have involvement in the src-family kinase pathway. [6] This astrocyte-neuron feedback has been proposed as a mechanism involved in CNS tissue repair post-injury, as a down regulation of thy-1 may lead to enhanced neurite outgrowth. Additional research has shown that thy-1 expression in post natal humans is elevated for several weeks. This suggests that in addition to tissue repair, thy-1 might have roles in early CNS tissue development and organization. [7] [8]

L1 family protein

The L1 family of proteins are involved in neuronal migration, as well as in axon growth and proper synapse formation, and include L1CAM, CHL1, NrCAM and neurofascin. L1-Cell Adhesion Molecule (L1CAM) was first discovered to be important in neuron-related tissue development in the mid-1980s, and is a trans-membranal glycoprotein of approximately 200-220 kDa. On its extracellular domain, the L1CAM protein includes IgG-like and fibronectin-III (FN-III) repeats which allow for interaction with integrins and ECM proteins. Similarly to integrin, F1CAM expresses domains intracellularly that interact with the actin cytoskeleton. Supporting the claim that L1-family proteins are involved in CNS development is the finding that L1CAM is highly expressed in neuronal tissue during its early stages of growth, especially at the ends of axons. Some areas of the brain, such as the hippocampus, have been found to highly express L1CAM into adulthood, though the exact reason for this has not been elucidated.

Due to its involvement in neuronal development and axon guidance, it has been proposed that L1CAM and L1-family proteins may be useful therapeutics to treat tissue damage in the CNS. Some have even proposed that L1CAM expression is elevated in vivo during tissue repair, which would support the notion that it yields benefit during CNS tissue repair. [9]

Mechanosensing in neurons

Mechanosensing is a process by which cells alter their bio-physical properties in response to mechanical cues present in the environment. It is well known that a wide-variety of cell types change their behavior to mechanical environmental signals.

In addition to providing force transmission to the ECM for neuron extension and development, Integrin mediated adhesions are also functional in these mechanosensing processes in neurons. Sensing of the external environments mechanical properties in vivo can determine cell behaviors such as differentiation and branching. It has been experimentally determined that increasing substrate stiffness (~2-80kPa) can result in sequestered neurite branching and branch length. [10] [11]

Relevant neurological conditions

Several debilitating diseases are brought about from errors in neural development due in part to problems involving neural cell adhesions and adhesion mechanisms.

Summary of CRASH conditions
YearComments
Corpus callosum hypoplasia Incomplete corpus-callosum development
RetardationImpaired cognitive function
Adducted thumbsAbnormal thumb development
Spastic paraplegia Stiffening and contraction in the lower limbs
Hydrocephalus Abnormal accumulations of Cerebrospinal fluid within skull

Related Research Articles

Axon Long projection on a neuron that conducts signals to other neurons

An axon, or nerve fiber, is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action potentials away from the nerve cell body. The function of the axon is to transmit information to different neurons, muscles, and glands. In certain sensory neurons, such as those for touch and warmth, the axons are called afferent nerve fibers and the electrical impulse travels along these from the periphery to the cell body and from the cell body to the spinal cord along another branch of the same axon. Axon dysfunction has caused many inherited and acquired neurological disorders which can affect both the peripheral and central neurons. Nerve fibers are classed into three types – group A nerve fibers, group B nerve fibers, and group C nerve fibers. Groups A and B are myelinated, and group C are unmyelinated. These groups include both sensory fibers and motor fibers. Another classification groups only the sensory fibers as Type I, Type II, Type III, and Type IV.

The development of the nervous system, or neural development, or neurodevelopment, refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The field of neural development draws on both neuroscience and developmental biology to describe and provide insight into the cellular and molecular mechanisms by which complex nervous systems develop, from nematodes and fruit flies to mammals.

Cell adhesion Process of cell attachment

Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indirect interaction, where cells attach to surrounding extracellular matrix, a gel-like structure containing molecules released by cells into spaces between them. Cells adhesion occurs from the interactions between cell-adhesion molecules (CAMs), transmembrane proteins located on the cell surface. Cell adhesion links cells in different ways and can be involved in signal transduction for cells to detect and respond to changes in the surroundings. Other cellular processes regulated by cell adhesion include cell migration and tissue development in multicellular organisms. Alterations in cell adhesion can disrupt important cellular processes and lead to a variety of diseases, including cancer and arthritis. Cell adhesion is also essential for infectious organisms, such as bacteria or viruses, to cause diseases.

Astrogliosis Increase in astrocytes in response to brain injury

Astrogliosis is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons from central nervous system (CNS) trauma, infection, ischemia, stroke, autoimmune responses or neurodegenerative disease. In healthy neural tissue, astrocytes play critical roles in energy provision, regulation of blood flow, homeostasis of extracellular fluid, homeostasis of ions and transmitters, regulation of synapse function and synaptic remodeling. Astrogliosis changes the molecular expression and morphology of astrocytes, in response to infection for example, in severe cases causing glial scar formation that may inhibit axon regeneration.

Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each other and to their surroundings. CAMs are crucial components in maintaining tissue structure and function. In fully developed animals, these molecules play an integral role in generating force and movement and consequently ensuring that organs are able to execute their functions normally. In addition to serving as "molecular glue", CAMs play important roles in the cellular mechanisms of growth, contact inhibition, and apoptosis. Aberrant expression of CAMs may result in a wide range of pathologies, ranging from frostbite to cancer.

L1 (protein)

L1, also known as L1CAM, is a transmembrane protein member of the L1 protein family, encoded by the L1CAM gene. This protein, of 200-220 kDa, is a neuronal cell adhesion molecule with a strong implication in cell migration, adhesion, neurite outgrowth, myelination and neuronal differentiation. It also plays a key role in treatment-resistant cancers due to its function. It was first identified in 1984 by M. Schachner who found the protein in post-mitotic mice neurons.

Axon guidance is a subfield of neural development concerning the process by which neurons send out axons to reach their correct targets. Axons often follow very precise paths in the nervous system, and how they manage to find their way so accurately is an area of ongoing research.

Netrin Class of proteins involved in axon guidance

Netrins are a class of proteins involved in axon guidance. They are named after the Sanskrit word "netr", which means "one who guides". Netrins are genetically conserved across nematode worms, fruit flies, frogs, mice, and humans. Structurally, netrin resembles the extracellular matrix protein laminin.

A neurite or neuronal process refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture, because it can be difficult to tell axons from dendrites before differentiation is complete.

CD90

Thy-1 or CD90 is a 25–37 kDa heavily N-glycosylated, glycophosphatidylinositol (GPI) anchored conserved cell surface protein with a single V-like immunoglobulin domain, originally discovered as a thymocyte antigen. Thy-1 can be used as a marker for a variety of stem cells and for the axonal processes of mature neurons. Structural study of Thy-1 led to the foundation of the Immunoglobulin superfamily, of which it is the smallest member, and led to some of the initial biochemical description and characterization of a vertebrate GPI anchor and also the first demonstration of tissue specific differential glycosylation.

Neuroregeneration refers to the regrowth or repair of nervous tissues, cells or cell products. Such mechanisms may include generation of new neurons, glia, axons, myelin, or synapses. Neuroregeneration differs between the peripheral nervous system (PNS) and the central nervous system (CNS) by the functional mechanisms involved, especially in the extent and speed of repair. When an axon is damaged, the distal segment undergoes Wallerian degeneration, losing its myelin sheath. The proximal segment can either die by apoptosis or undergo the chromatolytic reaction, which is an attempt at repair. In the CNS, synaptic stripping occurs as glial foot processes invade the dead synapse.

A nerve guidance conduit is an artificial means of guiding axonal regrowth to facilitate nerve regeneration and is one of several clinical treatments for nerve injuries. When direct suturing of the two stumps of a severed nerve cannot be accomplished without tension, the standard clinical treatment for peripheral nerve injuries is autologous nerve grafting. Due to the limited availability of donor tissue and functional recovery in autologous nerve grafting, neural tissue engineering research has focused on the development of bioartificial nerve guidance conduits as an alternative treatment, especially for large defects. Similar techniques are also being explored for nerve repair in the spinal cord but nerve regeneration in the central nervous system poses a greater challenge because its axons do not regenerate appreciably in their native environment.

PTPRM

Receptor-type tyrosine-protein phosphatase mu is an enzyme that in humans is encoded by the PTPRM gene.

NRCAM

Neuronal cell adhesion molecule is a protein that in humans is encoded by the NRCAM gene.

Collapsin response mediator protein family or CRMP family consists of five intracellular phosphoproteins of similar molecular size and high (50–70%) amino acid sequence identity. CRMPs are predominantly expressed in the nervous system during development and play important roles in axon formation from neurites and in growth cone guidance and collapse through their interactions with microtubules. Cleaved forms of CRMPs have also been linked to neuron degeneration after trauma induced injury.

Fasciclin 2 is a 95 kilodalton cell membrane glycoprotein in the immunoglobulin (Ig) – related superfamily of cell adhesion molecules (CAMs). It was first identified in the developing grasshopper embryo, seen dynamically expressed on a subset of fasciculating axons in the central nervous system (CNS), functioning as a neuronal recognition molecule in the regulation of selective axon fasciculation. Subsequently, fasII was cloned and has mainly been studied in the fruit fly. Its extracellular structure consists of two Fibronectin type III domains and five Ig-like C2 domains, having structural homology to the neural cell adhesion molecule (NCAM) found in vertebrates. Alternative splicing of fasII gives rise to its expression in three major isoforms, including a membrane-associated form that is attached to the outer leaflet of the plasma membrane via a glycophosphatidylinositol linkage and two integral transmembrane forms. The larger transmembrane form has an amino acid motif contained in its cytoplasmic domain that is rich in proline, glutamic acid, serine and threonine residues. The fasciclin 1 (Fas1) and fasciclin 3 (Fas3) genes in Drosophila also code for cell adhesion proteins in the nervous system but do not show any structural or functional similarities with NCAM.

A follower neuron is a nerve cell that arises in the developmental stage of the brain and which growth and orientation is intrinsically related to pioneer neurons. These neurons can also be called later development neurons or follower cells. In the early stages of brain development, pioneer neurons define axonal trajectories that are later used as scaffolds by follower neurons, which project their growth cones and fasciculate with pioneer axons, forming a fiber tract and demonstrating a preference for axon-guided growth. It is thought that these neurons can read very accurate cues of direction and fasciculate or defasciculate in order to reach their target, even in a highly dense axon bundle.

Neuronal self-avoidance

Neuronal self-avoidance, or isoneural avoidance, is an important property of neurons which consists in the tendency of branches arising from a single soma to turn away from one another. The arrangements of branches within neuronal arbors are established during development and result in minimal crossing or overlap as they spread over a territory, resulting in the typical fasciculated morphology of neurons.

Synaptic stabilization Modifying synaptic strength via cell adhesion molecules

Synaptic stabilization is crucial in the developing and adult nervous systems and is considered a result of the late phase of long-term potentiation (LTP). The mechanism involves strengthening and maintaining active synapses through increased expression of cytoskeletal and extracellular matrix elements and postsynaptic scaffold proteins, while pruning less active ones. For example, cell adhesion molecules (CAMs) play a large role in synaptic maintenance and stabilization. Gerald Edelman discovered CAMs and studied their function during development, which showed CAMs are required for cell migration and the formation of the entire nervous system. In the adult nervous system, CAMs play an integral role in synaptic plasticity relating to learning and memory.

Target selection is the process by which axons selectively target other cells for synapse formation. Synapses are structures which enable electrical or chemical signals to pass between nerves. While the mechanisms governing target specificity remain incompletely understood, it has been shown in many organisms that a combination of genetic and activity-based mechanisms govern initial target selection and refinement. The process of target selection has multiple steps that include Axon pathfinding when neurons extend processes to specific regions, cellular target selection when neurons choose appropriate partners in a target region from a multitude of potential partners, and subcellular target selection where axons often target particular regions of a partner neuron.

References

  1. Murase, S (Oct 1999). "The role of cell adhesion molecules in synaptic plasticity and memory". Current Opinion in Cell Biology. 11 (5): 549–53. doi:10.1016/s0955-0674(99)00019-8. PMID   10508654.
  2. Ridley, Anne (2003). "Cell Migration: Integrating Signals from Front to Back". Science. 302 (2003): 1704–09. doi:10.1126/science.1092053. PMID   14657486. S2CID   16029926.
  3. Kawauchi, T (2012). "Cell Adhesion and Its Endocytic Regulation in Cell Migration during Neural Development and Cancer Metastasis". International Journal of Molecular Sciences. 4. 13 (4): 4564–4590. doi: 10.3390/ijms13044564 . PMC   3344232 . PMID   22605996.
  4. Gullingsrud J, Sotomayor M. "Mechanosensitive channels". Theoretical and Computational Biophysics Group, Beckman Institute for Advanced Science and Technology: University of Illinois at Urbana-Champaign.
  5. Koch, Daniel (February 2012). "Strength in the Periphery: Growth Cone Biomechanics and Substrate Rigidity Response in Peripheral and Central Nervous System Neurons". Biophysical Journal. 102 (3): 452–460. doi:10.1016/j.bpj.2011.12.025. PMC   3274825 . PMID   22325267.
  6. Rege, Tanya (2006). "Thy-1, via its GPI anchor, modulates Src family kinase and focal adhesion kinase phosphorylation and subcellular localization, and fibroblast migration, in response to thrombospondin-1/hep I". Chronology. 312 (19): 3752–3767. doi:10.1016/j.yexcr.2006.07.029. PMID   17027000.
  7. Herrera-Molina, Rodrigo; et al. (May 2012). "Astrocytic aVb3 Integrin Inhibits Neurite Outgrowth and Promotes Retraction of Neuronal Processes by Clustering Thy-1". PLOS ONE. 3. 7 (3): e34295. doi: 10.1371/journal.pone.0034295 . PMC   3316703 . PMID   22479590.
  8. Barker, Thomas (2004). "Thy-1 regulates fibroblast focal adhesions, cytoskeletal organization and migration through modulation of p190 RhoGAP and Rho GTPase activity". Experimental Cell Research. 295 (2): 488–496. doi:10.1016/j.yexcr.2004.01.026. PMID   15093746.
  9. Schafer, Michael; Michael Frotscher (February 2012). "Role of L1CAM for axon sprouting and branching". Cell Tissue Res. 349 (1): 39–48. doi:10.1007/s00441-012-1345-4. PMID   22370595. S2CID   14454847.
  10. Man, Alan (2011). "Neurite Outgrowth in Fibrin Gels Is Regulated by Substrate Stiffness". Tissue Engineering. 17 (23 and 24): 2931–2942. doi:10.1089/ten.tea.2011.0030. PMID   21882895.
  11. Jiang, Frank (September 2008). "Neurite Outgrowth on a DNA Crosslinked Hydrogel with Tunable Stiffnesses". Annals of Biomedical Engineering. 36 (9): 1565–1579. doi:10.1007/s10439-008-9530-z. PMID   18618260. S2CID   20235247.
  12. Fransen E, Lemmon V, Van Camp G, Vits L, Coucke P, Willems PJ (1995). "CRASH syndrome: clinical spectrum of corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraparesis and hydrocephalus due to mutations in one single gene, L1". European Journal of Human Genetics. 3 (5): 273–84. doi:10.1159/000472311. PMID   8556302. S2CID   152852.
  13. Ruiz JC, Cuppens H, Legius E, et al. (July 1995). "Mutations in L1-CAM in two families with X linked complicated spastic paraplegia, MASA syndrome, and HSAS". Journal of Medical Genetics. 32 (7): 549–52. doi:10.1136/jmg.32.7.549. PMC   1050549 . PMID   7562969.
  14. Leifer, D (March 1992). "Thy-1 in hippocampus: normal anatomy and neuritic growth in Alzheimer's disease". Journal of Neuropathology & Experimental Neurology. 51 (2): 133–41. doi:10.1097/00005072-199203000-00003. S2CID   44912412.