A major mechanism involved in differentiation is induction, in which cells stimulate each other to develop in different ways.
Several landmark experiments that identified the role of induction in differentiation highlight how induction works through direct contact between cells in different tissues. Concluding by examining the role of induction through diffusion of molecular signals in pattern formation, the development of spatial organization of the differentiated parts of an animal.
Cytoplasmic segregation is the main mechanism underlying differentiation in early development, but the mechanism of induction becomes increasingly important in later stages.
In later phases of development, the fate of a cell depends more on its position in the embryo than on the nature of that cell’s own cytoplasm, because signals received from other cells become a dominant influence on gene expression. The importance of induction in development was discovered long before mechanisms of cell signaling and gene expression were understood.
In the early 20th century, Hans Spemann developed a technique for transplanting tissues from one embryo into another and performed a series of transplants on newts.
Because Spemann was interested in progressive determination, he transplanted tissues from embryos of different ages to see how this altered the fates of these tissues. For example, tissue that would normally become neural ectoderm would be transplanted to a region of a different embryo that would become epidermis. Spemann discovered that, if the transplant was done early enough, the transplanted piece of tissue would develop according to where it was transplanted instead of where it came from. For example, the transplanted neural ectoderm tissue became normal epidermal tissue.
However, Spemann found this result only if the transplant was done relatively early. If transplanted at a later time, tissue would not be determined by its locale but by its region of origin. Neural ectoderm tissue transplanted late enough would still become neural ectoderm tissue. Spemann’s work not only illustrated progressive determination, but it also showed the importance of location on determination, which is presumably caused by signals received from neighboring cells.
Spemann’s most important experiment was done in 1924, in collaboration with his young student Hilde Mangold.
They were interested in a region of the newt blastopore that appeared to become determined very early, and they predicted that this tissue would not change its fate even when transplanted very early in development. Mangold found, as predicted, that the transplanted tissue did not change its developmental fate; more surprisingly, she also observed that at the point where the transplanted tissue was attached, a new, second embryo arose. This second embryo was composed of cells derived from both the transplanted tissue and the original host. The transplanted cells had somehow altered the developmental fate of the cells around them.
In addition to dramatically illustrating how cells in one tissue can affect the developmental fate of the cells around them, this result indicated that particular regions in a developing embryo play a disproportionately important role in organizing the development of tissues around them. Spemann referred to these regions as organizers. Not all induction involves highly localized organizers, but since their discovery, many other organizers have been identified.
The lens of the vertebrate eye provides another example of how induction contributes to the development of a complex structure.
The lens is an extremely differentiated tissue that is specialized to transmit and focus light. It develops from ectodermal tissue—the same germ layer tissue that gives rise to skin and hair. In a frog embryo, for example, a region of the developing nervous system called the forebrain develops from an invagination of neural ectoderm tissue near the head-end of the animal. This neural ectoderm tissue bulges out at the sides to form optic vesicles, which will eventually form the nervous tissue associated with the eye. The optic vesicles expand until they come in contact with ectodermal cells on the outside of the embryo.
When the optic vesicles come in contact with the undifferentiated outer ectoderm, the region of contact begins to thicken, forming a lens placode, which is the precursor to the lens itself. It is possible to demonstrate that optic vesicle tissue induces the outer ectoderm to form the lens placode and, ultimately, the lens by removing the vesicle or inserting a sliver of plastic between it and the ectoderm. In both cases, the lens fails to develop. This result also indicates that some molecular signal must pass from the optic vesicle to the ectoderm.
Another feature of induction illustrated by lens development is that induction is often reciprocal.
Once the lens has formed, it induces the optic vesicle to further differentiate into the optic cup, one part of which develops into the retina. The lens also induces other ectodermal cells on the outside of the embryo to become the cornea of the eye. The most important point to be made is that induction often involves sequences of reciprocal interactions among different tissues in the developing organism. For example, the specific placement of the lens depends on the precise position of the optic vesicle; thus, it makes sense that the optic vesicle should induce lens formation.
The determination and differentiation of cells into functionally different cell types is only one part of what is needed to build the complex structure of a multicellular organism.
The front and rear legs of a cat are made of the same kinds of cells and tissues but are very different in shape and, of course, work in different ways. The difference between these two kinds of limbs is a consequence of their tissues’ arrangement in space, not the different kinds of tissues they contain. The development of the spatial organization of the parts of an animal is called pattern formation. Pattern formation involves induction, but all the examples we have seen involved direct contact between the interacting tissues. In some cases, however, signals spread more widely through the developing organism; because these signals may diffuse across wide stretches of tissue, they create signal gradients within those tissues. These gradients of molecular signals can then provide developing cells with information about their relative position in the embryo; these cues are also called positional signals.
The development of a chicken wing provides a useful example illustrating the functioning of positional signals.
Vertebrate limbs begin as undifferentiated limb buds, small expanses of tissue protruding from the main axis of the trunk of the developing embryo. Each bone, muscle, and other component of a limb will arise, in a precise three-dimensional arrangement, from this lump of ectodermal and mesodermal tissue. Embryonic tissues in a wing bud somehow receive information indicating what part of the limb they should turn into, depending on where they are located in that limb. One model suggests that particular regions of the limb serve as organizers that provide information about relative position to developing cells by secreting diffusible molecular signals. The relative orientation of parts of a chicken wing is similar to that of a human hand in that both have important asymmetries along the proximal-distal (fingertips-to-wrist), anterior-posterior (thumb-to-little finger), and dorsal-ventral (palm-to-back of the hand) axes.
In chickens, differentiation along the proximal-distal axis appears to be controlled at least in part by an organizer region located on the outermost tip of the developing wing bud.
This region is called the apical ectodermal ridge, or AER. The AER secretes several proteins that act as growth factors by inducing cell division. If the AER is surgically removed, the limb stops growing; if it is transplanted elsewhere, a new limb will be induced there. Even more significantly, if the AER is removed at different times, it does not simply produce smaller limbs; instead, the limbs will lack distal parts. This suggests that the AER produces a molecular signal that helps specify position along the proximal -distal axis. The AER does not appear to work alone but in conjunction with an area of tissue immediately beneath it called the progress zone. Reciprocal signaling between these regions is responsible for patterning along the proximal-distal axis. The exact mechanism by which the progress zone and AER specify the proximal-distal axis is still the subject of considerable research and debate.
A second major limb-bud organizer region, and a better-understood one, is the zone of polarizing activity, or ZPA.
The ZPA is located near the base of the limb bud, on the posterior side. One model suggests that the ZPA produces a molecular signal that diffuses throughout the limb bud. This hypothesis was tested experimentally by transplanting the ZPA from one chick to an incorrect position on the developing wing of another chick and observing the results. A second ZPA added to the anterior margin of a wing bud produced two sets of digits, which were mirror images of each other along the anterior-posterior axis (like two human hands joined at the thumbs).
When a substance diffuses away from a fixed source, the concentration of that substance is higher closer to the source and diminishes steadily as you move away from the source. The concentration of ZPAproduced signals is particularly high on the posterior side of the limb bud and increasingly lower in the anterior direction; this concentration gradient “tells” cells where they are in the limb bud along the anteriorposterior axis. Cells near the transplanted ZPA received positional information indicating that they were on the posterior side and, thus, were induced to produce posterior structures.
Though it is clear that signals produced by cells induce development, much is still unknown about how other cells receive these signals and how these signals influence gene regulation, even in a well-understood system, such as a chicken.
Sources: 1
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