Lecture5/6
Apoptotic cell death during developmental and during adult tissue
homeostasis:
A. Development: Genetic basis of cell death in C. elegens development,
examples of PCD in mammalian neuronal development, and inter-digital cell
death during development and metamorphosis.
B. Tissue homeostasis: Cellular homeostasis in blood cells, immune system,
epithelial
cells, hormone dependent changes in tissue architecture such as
those in breast and uterine tissues.
C. Physiological cell death as safeguard against growth of cells carrying
mutations (potentially capable of becoming cancerous)
Example of programmed cell death during development:
a) C.elegens development: ced-3 and ced-4 genes encode pro-apoptotic
proteins. These proteins are required for cell death. Mutation in these
genes led to the prevention of death of 131 cells of the c. elegeans and
the worm developed unusually but survived. But if the ced-9 gene was
defective, all the cells died and so did the embryo. The ced-9 encodes an
anti-apoptotic protein. It is required in the other cells to prevent cell death
(Ellis R E and Hoevitz (1986) Cell, 44: 817-819, Yuan, J and Horvitz, H. R.
(1990) Dev. Biol. 138: 33-41).
b) In vertebrates:
Metamorphosis: Cells in the tadpole tail are triggered to die by thyroid
hormone secreted by thyroid gland. Similarly the intestine of tadpole is totally
degenerated by apoptosis induced by Thyroid hormone. Apoptosis can be
induced by adding to the epithelial cultures from tadpole. TH responsive
gene expression----matrix metalloproteases were expressed in response to
TH hormone (Patterton et al. (1995) Devel. Biol. 167:252-262).
Neuronal cell death during development (Johnson EM and Deckwerth TL
(1993) Annual Rev. Neurosci. 16:31-46).
Peptide inhibitors of caspase-1 arrested apoptosis of motor neurons in vivo
(Milligan et al, 1995, Neuron, 15 : 385-393)
Transgenic caspase-3 knockout mice, died post-natally (Kuida et al (1996)
Nature, 384: 368-372.
Large scale astrocyte death in developing cerebellum
More than 50% oligodendrocytes die during developing rat optic nerves.
Culture of oligodendrites require factors secreted by optic nerve cells. They
could be rescued by PDGE or IGF-1(Barres et al 1992, Cell 70:31-46).
Other culture models: Differentiation of PC-12 cells into neuronal cells by
NGF. The differentiated cells depend on NGF for survival. Removal of NGF
triggers apoptosis in these cells.
Tissue homeostasis:
Requirement of survival signals: Prostrate cells require testosterone to
survive.
Cells in adrenal cortex depend on ACTH secreted by pituitary gland.
Interlukin-2 dependent T- lymphoblast cells require IL-2 for survival
Endothelial cells require fibroblast growth factors (FGF) for survival
Game of cell proliferation and cell death in Immune system:
T lymphocytes: Responsible for cell mediated immunity
Cytotoxic T cells or killer T cells
Helper T cells: produce IL-2, and activate other lymphocytes
B lymphocytes: Mount antibody response against antigens
Lymphocyte maturation in Thymus
Cells expressing no receptor and cells expressing high affinity to self antigens
are induced to undergo apoptosis
Cells expressing receptors for foreign antigen and low affinity for self antigens
survive and are released in circulation- resting T cells
When they encounter antigen ----they get actvated-----proliferate, synthesize
lymphokines, produce perforin and grazyme B as well as non-functional Fas
receptor and ligand
This leads to removal of antigen
After the antigen is gone---now unnecessary cells are induced to undergo
apoptosis by 1. Deprivation of IL-2 survival signal or 2. by making functional
fas receptor and ligand, and inducing cell death