Biology Reference
In-Depth Information
innervation of targets has begun, neurons become highly dependent on target-derived neuro-
trophins and, if they do not receive enough, they undergo elective cell death. Neurons whose
axons have failed to make contact with a suitable target will certainly die, and those that have
reached a potential target will compete with each other for survival. The size of the neuronal
pool is therefore adjusted automatically for the size of its target.
The dependence of the survival of one tissue type on the presence of another seems to be
a general feature of development. In the kidney, for example, the survival of the mesenchyme
depends on growth factors such as FGFs that are secreted by the epithelial ureteric bud.
52
e
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In the foetal liver, the survival of red blood cell precursors depends on circulating levels of
erythropoietin,
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which is made mainly in the developing kidneys and in the liver itself.
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Erythropoietin is made in response to an increased demand for blood cells, so the apoptotic
mechanism is used as an alternative means of population control
(alternative to
proliferation).
ANOIKIS AND ERROR CORRECTION
No morphogenetic process is perfect, and accumulated errors in any of the processes
described in this topic can result in a developmental mistake, typically a cell finding itself
where it ought not to be. Simple probability makes this particularly relevant to the devel-
opment of organisms such as mammals because they have many cells and their morpho-
genesis involves a great deal of cell migration and movement. As well as relying for their
survival on diffusible signals such as growth factors, many cells also rely on survival
signals transduced by specific matrix receptors. These two pathways connect so that
they effectively perform a Boolean AND operation, cells surviving only if they receive
soluble survival factors and matrix signals. This allows cells to detect, at high spatial
resolution, whether they are placed correctly and to kill themselves if they are not. Elec-
tive cell death caused by displacement from a normal tissue environment is called
'anoikis'.
)
Anoikis was first discovered when the interaction between renal epithelial cells and their
basement membrane was interrupted, using competitive peptides. The cells underwent elec-
tive cell death, unless they were 'transformed' beforehand by transfection with constitutively-
active forms of enzymes, such as Src or focal adhesion kinase (FAK), that normally transduce
signals from cell-matrix adhesion complexes.
56,57
Subsequent work has revealed a number of
different intracellular pathways that are used to link the cell matrix with survival, including
PI-3-kinase, Erk, Rac/Rho/cdc42 and Jun kinase.
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All of the cells of a simple epithelium (Chapter 15) maintain contact with the basement
membrane. If any cell becomes displaced, either through damage or through a misalignment
of mitosis, it will lose contact with the membrane and will therefore undergo elective cell
death. This facility is probably an important mechanism by which animals guard against
the possibility of epithelial cells piling up in a way that would block tubes, and so on. It
is striking how many cancer pathways are associated with the mutation of signalling
)
From the ancient Greek for 'homelessness'.
