Cell Death and the Formation of Digits and Joints

Sculpting the autopod

Cell death plays a role in sculpting the limb. Indeed, it is essential if our joints are to form and if our fingers are to become separate (Zaleske 1985). The death (or lack of death) of specific cells in the vertebrate limb is genetically programmed and has been selected for during evolution. One such case involves the webbing or nonwebbing of feet. The difference between a chicken's foot and that of a duck is the presence or absence of cell death between the digits (Figure 16.22A,Figure 16.22B). Saunders and co-workers (1962; Saunders and Fallon 1966) have shown that after a certain stage, chick cells between the digit cartilage are destined to die, and will do so even if transplanted to another region of the embryo or placed into culture. Before that time, however, transplantation to a duck limb will save them. Between the time when the cell's death is determined and when death actually takes place, levels of DNA, RNA, and protein synthesis in the cell decrease dramatically (Pollak and Fallon 1976).

Figure 16.22

Patterns of cell death in leg primordia of (A) duck and (B) chick embryos. Shading indicates areas of cell death. In the duck, the regions of cell death are very small, whereas there are extensive regions of cell death in the interdigital tissue of the (more...)

In addition to the interdigital necrotic zone, there are three other regions that are “sculpted” by cell death. The ulna and radius are separated from each other by an interior necrotic zone, and two other regions, the anterior and posterior necrotic zones, further shape the end of the limb (Figure 16.22B; Saunders and Fallon 1966). Although these zones are said to be “necrotic,” this term is a holdover from the days when no distinction was made between necrotic cell death and apoptotic cell death (seechapter 6). These cells die by apoptosis, and the death of the interdigital tissue is associated with the fragmentation of their DNA (Mori et al. 1995).

The signal for apoptosis in the autopod is probably provided by the BMP proteins. BMP2, BMP4, and BMP7 are each expressed in the interdigital mesenchyme, and blocking BMP signaling (by infecting progress zone cells with retroviruses carrying dominant negative BMP receptors) prevents interdigital apoptosis (Figure 16.23A; Zou and Niswander 1996; Yokouchi et al. 1996). Since these BMPs are expressed throughout the progress zone mesenchyme, it is thought that cell death would be the "default" state unless there were active suppression of the BMPs. This suppression may come from the Noggin protein, which is made in the developing digits and in the perichondrial cells surrounding them (Figure 16.23B; Capdevila and Johnson 1998; Merino et al. 1998). If noggin is expressed throughout the limb bud, no apoptosis is seen.

Figure 16.23

Blocking the BMP receptor can prevent apoptosis in the chick autopod. (A) The left limb bud was untreated, while the right limb bud was infected with a virus that transcribed a dominant negative BMP receptor. This mutant receptor blocked BMP signaling (more...)

Forming the joints

The function originally ascribed to BMPs was the formation, not the prevention, of bone and cartilage tissue. In the developing limb, BMPs induce the mesenchymal cells either to undergo apoptosis or to become cartilage-producing chondrocytes—depending on the stage of development. The same BMPs can induce death or differentiation, depending on the age of the target cell. This “context dependency” of signal action is a critical concept in developmental biology. It is also critical for the formation of joints. Macias and colleagues (1997) have shown that during early limb bud stages (before cartilage condensation), beads secreting BMP2 or BMP7 cause apoptosis. Two days later, the same beads cause the limb bud cells to form cartilage.

In the normally developing limb, BMPs use both these properties to form joints. BMP7 is made in the perichondrial cells surrounding the condensing chondrocytes and promotes cartilage formation (Figure 16.24A; Macias et al. 1997) . Two other BMP proteins, BMP2 and GDF5, are expressed at the regions between the bones, where joints will form (Figure 16.24B; Macias et al. 1997; Brunet et al. 1998). Mouse mutations have suggested that the function of these proteins in joint formation is critical. Mutations of Gdf5 produce brachypodism, a condition characterized by a lack of limb joints (Storm and Kingsley 1999). In mice homozygous for loss-of-function alleles of noggin, no joints form, either. It appears that the BMP7 in these noggin-defective embryos is able to recruit nearly all the surrounding mesenchyme into the digits (Figure 16.24C,Figure 16.24D; Brunet et al. 1998). The roles of BMP2 and GDF5 are more controversial. They may either be destroying mesenchymal cells to form the joint or inducing them to rapidly differentiate and join one or the other cartilaginous nodule. In either way, a space is made between the nodules, and a joint can form.

Figure 16.24

Possible involvement of BMPs in stabilizing cartilage and forming joints. (A, B) Expression pattern of (A) BMP7 and (B) BMP2 in two consecutive microscopic sections of chick digits III and IV during a late stage of limb formation. The asterisks in (A) (more...)

Limb development is an exciting meeting place for developmental biology, evolutionary biology, and medicine. Within the next decade, we can expect to know the bases for numerous congenital diseases of limb formation, and perhaps we will understand how limbs are modified into flippers, wings, hands, and legs.

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Sculpting the autopod

Figure 16.22

Figure 16.23

Forming the joints

Figure 16.24

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