Programmed cell death

2 m Apoptosis of a human white blood cell.

Dr H. Gutierrez

Cell biology: Week 9, Nov 2012

Apoptosis during the metamorphosis of a tadpole into a frog As a tadpole changes into a frog, the cells in the tadpole tail are induced to undergo apoptosis; as a consequence, the tail is lost. All the changes that occur during metamorphosis, including the induction of apoptosis in the tail, are stimulated by an increase in thyroid hormone in the blood.

Figure 11.22

Interdigital tissue

Cells undergoing apoptosis

1 mm

Space between digits

Sculpting the digits in the developing mouse paw by apoptosis The paw in this mouse embryo has been stained with a dye that specifically labels cells that have undergone apoptosis. The apoptotic cells appear as bright green dots between the developing digits. This interdigital cell death eliminates the tissue between the developing digits, as seen one day later, when few, if any, apoptotic cells can be seen. (From W. Wood et al., Development 127:5245–5252, 2000. © The Company of Biologists.)

Postmitotic neuronal development is controlled by numerous signalling molecules derived from a wide variety of neighbouring and distant cells

Neural crest
Target Region

NGF

C A

B

Target field

NGF
D, E

Disruption of normal brain development by blocking apoptosis. In mice in which caspase-9 or Apaf-1 has been knocked out, normal neural apoptosis fails to occur. In caspase 9-deficient mice, the overproliferation of brain neurons is obvious on a morphological level. (FromKuida et al. 1998.) Developmental Biology. 6th edition.
Gilbert SF. Sunderland (MA): Sinauer Associates; 2000.

Apoptosis
Form of cell death, also known as programmed cell death, in which a ‘suicide’ program is activated within the cell, leading to fragmentation of the DNA, shrinkage of the cytoplasm, membrane changes and cell death without lysis or damage to neighboring cells. It is a normal phenomenon, occurring frequently in a multicellular organism.

Programmed cell death
• Apoptosis prunes away unneeded structures and tissues transiently needed during development. • Controls the number of cells in particular tissues
• Sculpts complex organs during development. • Each day we loose 1011 cells through programmed cell death.

Apoptosis Is Mediated by an Intracellular Proteolytic Cascade

Cell death These electron micrographs show cells that have died by (A) necrosis or (B and C) apoptosis. The cells in (A) and (B) died in a culture dish, whereas the cell in (C) died in a developing tissue and has been engulfed by a neighboring cell. Note that the cell in (A) seems to have exploded, whereas those in (B) and (C) have condensed but seem relatively intact. The large vacuoles visible in the cytoplasm of the cell in (B) are a variable feature of apoptosis. (Courtesy of Julia Burne.)

Activation of apoptosis from outside the cell (extrinsic pathway)

Induction of apoptosis by extracellular stimuli Extracellular activation. A killer lymphocyte carrying the Fas ligand binds and activates Fas proteins on the surface of the target cell. Adaptor proteins bind to the intracellular region of aggregated Fas proteins, causing the aggregation of procaspase-8 molecules. These then cleave one another to initiate the caspase cascade.

Activation of apoptosis from inside the cell (intrinsic pathway)

Induction of apoptosis by intracellular stimuli Intracellular activation. Mitochondria release cytochrome c, which binds to and causes the aggregation of the adaptor protein Apaf-1. Apaf-1 binds and aggregates procaspase-9 molecules, which leads to the cleavage of these molecules and the triggering of a caspase cascade. Other proteins that contribute to apoptosis are also released from the mitochondrial intermembrane space (not shown).

The caspase cascade involved in apoptosis

Each suicide protease is made as an inactive proenzyme (procaspase), which is usually