Biology Reference
In-Depth Information
FIGURE 22.11
The growth plates of developing human long bones. Most proliferation takes place in a zone just
proximal to the stem cells (which proliferate only enough to maintain their own numbers); this zone is coloured
dark blue in the diagram. Cells within the growth plate are arranged in longitudinal columns so that they 'flow'
towards the shaft itself as they expand and differentiate. The contribution of new cells to the shaft drives elongation
of the bone.
are zones at the ends of the shaft of each bone at which new bone formation takes place
(
Figure 22.11
). Events in the growth plates are complex, involving the proliferation, differen-
tiation and death of cells,
57
but only proliferation will be considered here.
The global signals provided by GH are 'translated' into local signals carried by IGFI and
IGFII at the growth plate itself.
58
e
60
IGFI and IGFII are both potent stimulators of chondro-
cyte proliferation,
61
so that the level of circulating GH controls the proliferation of cells
within the growth place. Some effects of GH on the growth plate are mediated by a local sig-
nalling loop that uses the peptide PTHrP and the signalling molecule Ihh. The importance of
this loop for body symmetry will be considered later in this chapter.
57
GH may also have
a direct effect, as well as an indirect one via other growth factors.
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The IGF signalling pathway is very important in the size regulation of mammalian tissues
in general. Mice lacking IGF1 or lacking IGF2 are born very small and cannot be rescued by
injections of GH.
63
e
65
Those lacking the receptor for IGF1 show an even greater defect of
growth and generally die around birth.
65,66
The use of IGFs to regulate organ size is also
highly conserved across the animal kingdom. Mutants of Drosophila melanogaster that have
reduced function of dINR, the insect's homologue of the IGF receptor, are half the weight
of normal flies and this reflects a reduction in both cell size and cell number. Conversely,
mutants that show over expression of ligands for dINR are, on the other hand, significantly
larger than normal flies.
67
The fact that both cell size and cell number are affected by mutation of the IGF signalling
pathway in D. melanogaster is especially interesting, in the light of the ability of embryos
to compensate for proliferation defects using cell size and vice versa. The size regulation
mechanism that can use cell size to compensate for defective proliferation must itself be liable
to mutation, and the expected phenotype would be failure of this compensation. Such
mutants exist, and include the genes PTEN, tuberous sclerosis, InR, Akt and chico.
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e
70
All of
these are components of the IGF signal-transduction pathway (
Figure 22.12
). Loss-of-func-
tion mutants of the positive regulators of this pathway, such as InR, PI-3-Kinase, and s6k,
all lead to smaller cells and organs, while loss-of-function mutations of repressors of the
pathway, such as PTEN, result in abnormally large organs (some of these data come from
