174 C
.H. Knight Livestock Production Science 66 2000 169 –176
not only was apoptosis turned off, but cell prolifer- tricably linked and that induction of apoptosis re-
ation was also turned on in order to recover the quires not only an initial signal causing cells to enter
lactation. This very neat picture is, however, incom- the cell cycle but also the subsequent absence of a
plete. Whilst bromodeoxyuridine incorporation was survival signal which would otherwise ‘‘rescue’’ the
highest during resuckling, it was also elevated above cell. This reduces the likelihood of inappropriate
control levels during the separation period, i.e., when proliferation i.e., cancer since two mutations would
apoptosis was up-regulated and, we would have have to occur to achieve the desired combination of
anticipated, proliferation was firmly turned off signals, but it also provides the necessary means by
Table 1. This raises the intriguing possibility that, which mammary involution can be rapidly reversed.
faced with the absence of her pups, the lactating mouse decides to turn off lactation but does so in
such a way that a fresh population of secretory cells
5. Cell survival and lactation length
will be readily recruitable should she have the need of them. Whilst it is possible that the same cue which
During the separation period, milk collected from starts apoptosis also starts a totally different series of
the mice contained high levels of one particular IGF events leading to cell proliferation, a more likely
binding protein, IGFBP-5. This binding protein has explanation is given in Fig. 3, which puts apoptosis
previously been observed in involuting mammary into the context of the cell cycle. It may be that
tissue Tonner et al., 1995 and was not present in terminally-differentiated cells can enter directly into
milk from control or resuckled mice. IGF-1 is a apoptosis, but there is also evidence to show that
known mammary mitogen and has been implicated they do not do this, but rather that they re-enter the
as a mammary cell survival factor see Flint and cell cycle, synthesise DNA at which point they
Knight, 1997, but its concentration is paradoxically would incorporate bromodeoxyuridine and then
elevated during post-lactational involution. In the undergo apoptosis Colombel et al., 1992. Assum-
presence of IGFBP-5, however, the cell survival ing there is a ‘‘switch’’ at this point, the resumption
function is lost. The post-lactational appearance of of suckling would act to divert these cells away from
IGFBP-5 is prevented by administration of the the apoptotic path and keep them in a proliferative
suckling-related hormone, prolactin Tonner et al., cell cycle. The ‘‘dual-signal’’ hypothesis of Evan and
1995, so it would appear that all the necessary Littlewood 1993 envisages exactly this. They claim
elements of the dual-signal hypothesis are present. that apoptotic and proliferative pathways are inex-
IGF-1 possibly produced locally via GH stimulation of mammary endothelial cells causes cells to enter
the cell cycle and, if suckling occurs, prolactin is released, IGFBP-5 is down-regulated and the cell
survival activity is turned on. When suckling is prevented, the cells lose their survival signal and
apoptosis results, to be replaced by survival when suckling is restored Fig. 3.
Although this model has been developed in ro- dents, there is no reason to believe that it does not
also operate in dairy species, although it is important to recognise that the time course of events may be
very different, since mammary involution is a much
Fig. 3. Schematic representation of the cell cycle to show the
slower process in cows than in mice Wilde et al.,
possible routes to apoptosis. M: Mitosis. S: DNA synthesis. In the
1997. We are beginning to study lactation rescue in
absence of continued suckling, differentiated mammary secretory
cows. The potential benefits of being able to unravel
cells may enter directly into apoptosis or, more likely, re-enter the
the mechanisms controlling cell proliferation and
cell cycle, synthesise DNA and then either undergo apoptosis or, if suckling is resumed, proliferate.
apoptosis in the lactating gland are immense. As I
C .H. Knight Livestock Production Science 66 2000 169 –176
175
stated earlier, apoptosis usually exceeds proliferation, ADAS Bridgets Research Centre, funded by the Milk
so there is a gradual loss of secretory cells and a Development Council and BOCM Pauls Ltd.
consequent reduction in milk yield. For this reason, dairy farmers have to rebreed their cows regularly
and the cows have to cope with the dual metabolic
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Hormone-regulated apoptosis results from re-entry of differen-
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even at all. The benefits of extended lactation have
Dewhurst, R.J., Mitton, A.M., Knight, C.H., 1993. Calibration of a polyurethane foam casting technique for estimating the weight
been considered previously Knight, 1997.
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6. Conclusions
