Posted by: Dan | April 27, 2006

Cell Migration primer

Migration 101 (as shown on the Cell Migration Gateway)
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Overview

Directed cell migration accompanies us from conception to death. This integrated process choreographs the morphogenesis of the embryo during development. The failure of cells to migrate or migration of cells to inappropriate locations can result in life threatening consequences such as the congenital defects prominent in the brain. In the adult, cell migration is central to homeostatic processes such as mounting an effective immune response and the repair of injured tissues. It contributes to pathologies including vascular disease, chronic inflammatory diseases, and tumor formation and metastasis. Understanding cell migration is also becoming important to emerging areas of biotechnology which focus on cellular transplantation and the manufacture of artificial tissues.

Embryonic Development

We all began life as a single, genetically complete cell (zygote), resulting from the union of a sperm and egg cell. After conception the zygote contains the entire genetic blue print for the life of a new individual and quickly becomes a ball of rapidly dividing cells called a blastocyst. When the blastocyst arrives in the uterus, it invades and migrates into the uterine wall in order that a placenta may develop to nourish the developing embryo. While this is occurring migration related proteins are also instructing large groups of cells inside the blastocyst to migrate to form layers, a process called gastrulation. Cells within these layers eventually migrate to strategic locations along the developing embryo where they specialize and become components of arms, legs, liver, heart, brain and other organs. In the developing brain, for example, primitive neuronal cells migrate to reside in distinct layers where they begin to send projections (axons and dendrites) through the layers of developing cells to their final targets where they form specific connections, called synapses, that allow complex functions like learning and memory. It is important to realize that the developmental process does not simply refer to the first 9 months of our existence, but is a process which continues for the rest of our lives, as some cells through out our bodies are born, migrate, mature and die on a daily basis. The process of cell migration as it relates to development literally accompanies us from conception to death.

More information about early development

Homeostasis

Immunity and wound healing are two homeostatic processes in the body that rely on the ability of cells to migrate. Neither of these processes would be possible if it were not for migration, and often they occur together. For example, when you cut yourself, the process of wound healing is initiated to repair the damage. Cells of the immune system are recruited to dispose of invading bacteria and other microorganisms entering through the wound. Cells proliferate and migrate to fill the wound. If bacteria opportunistically entered through the wound, white blood cells (leukocytes) from the circulation migrate into the surrounding tissue to destroy them. The bacteria are engulfed by the white blood cells, where potent digestive enzymes destroy them. Immune cells are constantly on surveillance duty, circulating throughout the body looking for foreign material to attack and destroy, and thus it is important for these cells to develop a sense of self so that they can recognize the bodies own cells and not destroy them. This sense of self is established early on in their development as they migrate through the primary lymphoid tissues of the bone marrow and thymus.

Pathobiology

An array of different migration related proteins have been shown to be critical for embryonic and fetal development. Defects in these proteins can be manifest very early on as a failure of blastocyte implantation into the uterus, resulting in early loss of pregnancy. Defects in the migration proteins involved later on in development can result in malformed embryos, where tissues are disorganized because their component cells have failed to travel to their appropriate location or despite having traveled appropriately they fail to form the appropriate connections with neighboring cells and their surroundings. Those defects that do not result in early fetal death can lead to a number of congenital abnormalities in brain development resulting in epilepsy, focal neurological deficits and mental retardation.

Migration related proteins are involved in our everyday life through many normal processes but when problems arise in these processes, pathologies develop. When immune responses continue indefinitely, they result in chronic inflammatory conditions where migration related proteins appear to play a pivotal role. Asthma is a chronic inflammation of the airways resulting from an ongoing immune response to foreign materials (allergens) inhaled from the environment. The constant presence and activation of white blood cells in the airways (lungs) of asthmatics causes tissue damage resulting in hyper-reactivity of the airways to otherwise innocuous stimuli such as exercise, stress and cold air. In rheumatoid arthritis, the constant destruction of joint tissue by inflammatory cells migrating into these compartments as part of an autoimmune disorder, results in compromised limb function and crippling pain.

Basic Migration Mechanics

Migration is a dynamic, cyclical process in which a cell extends a protrusion at its front, which in turn attaches to the substratum on which the cell is migrating. This is followed by a contraction that moves the cell body forward toward the protrusion, and finally the attachments at the cell rear release as the cell continues to move forward. The cycle is initiated by external signals (chemotactic molecules), which are sensed and communicated to the cell’s interior by specialized receptive proteins in the cell membrane. In response to these signals, cells extend protrusions, by polymerizing actin, that act as feelers, seeking out new terrain and sensing the direction from which they are receiving signals. Once the direction for movement is established the machinery for enabling movement assembles with regard for the direction of migration. Adhesive complexes needed for traction collect at the front of the protrusion, tethering the protrusion to the substratum. Actomyosin filaments contract at the front of the cell and pull the cell body toward the protrusion. Release of adhesive connections in the rear of the cell and retraction of the tail completes the cycle. The orchestration of this complex process resides in many molecules that serve to distinguish the front from the rear of the cell and whose actions are carefully timed.

Further Reading

  • Cell migration–movin’ on. Horwitz AR, Parsons JT. Science. (1999) 286:1102-3. PubMed
  • Cell migration: a physically integrated molecular process. Lauffenburger DA, Horwitz AF. Cell. (1996) 84:359-69. PubMed
  • Cells into Organs; the forces that shape the embryo. Trinkaus, JP. Second Edition Prentice-Hall Inc., ISBN# 0-13-121632-5.
  • For more detailed reading please go to Review papers
  • See a movie of a moving cell

Other useful sites


Responses

  1. Nice site – I look forward to more posts.

    I did some postgrad research into cell migration in the developing chick cerebellum. The work involved trying to determine the cues governing the migration of cerebellar granule cells.

    As you know, cell migration is controlled by permissive, non-permissive and repulsive cues which together guide cells to their destination. Axon guidance also involves similar mechanisms, although the cues are detected
    by the growth cone of the extending neurite rather than the cell body.

    During neural development, most cell types are generated by division in the ventricular zone of the pseudostratified neuroepithelium. Once generated, they undergo a radial migration perpendicular to the longitudinal axis of the neural tube. The cerebral cortex is formed in this way – its layers are generated in an ‘inside-out’ manner, such that the first wave of migrating cells form the inner layers, and so on.

    Precursors of cerebellar granule cells, however, undergo a unique migration. They are generated in the rhombic lip, a tissue found at the interface between the dorsal neuroepithelium and the roof of the fourth ventricle. These cells first undergo a tangential migration along the dorsal surface of the neural tube and then a radial migration. Whereas the radial migration of other neural precursors is centripetal (from the inside of the neural tube outwards), that of granule cell precursors is centrifugal (from the surface of the neural tube inwards).

    Part of my project involved cloning a fragment of an axon guidance molecule called Slit2, which has been implicated in the migration of granule cells. I designed primers from the DNA sequence of the mouse Slit gene; these primers were then used to clone an approximately 2 kilobase fragment of the chick homolog of the gene from a chick cDNA library.

    Neural crest cells also undergo interesting migrations. They originate at the dorsolateral aspect of the neural tube and migrate throughout the body of the organism. They form many different structures, including cells of the peripheral nervous system.

    My work on cerebellar granule cell precursor migration was carried out at Guy’s medical school. The project was a PhD thesis which I never completed.

  2. Thanks,
    Aspects of neural development and axon guidance is another thing that I’m specifically looking at reading up on, and in the process, discussing on here at some point by covering a few reviews. But up to this point, I’ve only skimmed the surface on that topic.

    Slit2 sounds interesting though – some questions:

    • What suggested that Slit2 might be involved in the centrifugal granule cell migration?
    • What did you (or going to) use the chick homolog fragment to examine?
    • And, if you don’t mind me asking, why weren’t you able to finish your PhD? (you don’t have to answer that if you don’t want to)

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