Summary
We recently demonstrated that expression of V600EBraf in mature mouse melanocytes induces melanoma. Here, we show that expression of V600EBraf using the tyrosinase promoter leads to an ...unexpected embryonic lethality, with the animals dying before, at, or shortly after birth. The mice suffer from a range of developmental defects in the skin, the brain, the eyes and the heart, tissues that are normally colonized by melanocytes. We show that the V600EBraf expressing cells are potential melanocytic precursors that are fully transformed, suggesting that V600EBraf stimulates proliferation and blocks differentiation of these cells. Our data suggests that the presence of these cells in the organs that are normally occupied by melanocytes leads to severe developmental disruption, resulting in catastrophic defects and leading to death of the individual.
The internal mammalian body plan is laterally asymmetric with a consistent handedness such that some organs are placed on one side (stomach on the left, for example) and paired organs are not ...symmetric (for example, there are more lung lobes on the right). Some chemical teratogens can affect the development of asymmetry, and some can cause asymmetric defects in overtly symmetric structures, but the mechanisms are unknown. We have used chemical treatment of rat embryos in culture to examine the stage at which the left-right axis is determined and show that all effective treatments can affect left-right axis development up to the early headfold stage, but not from late headfold onwards. This suggests that the left-right axis is determined by the late headfold stage, even though the embryo is overtly symmetric at this stage. It appears to be much easier to induce an abnormal left-right axis from late allantoic bud and early headfold stages; than the early allantoic bud stage, but we have not established the earliest stage at which a response can be induced. Complete
situs inversus was the most common chemically induced abnormality, although heart looping and body turning could be inverted separately, suggesting that the two phenomena are linked but not wholly interdependent. The treatments appeared to cause a loss of handedness, rather than inducing inversion, since the incidence of an abnormal left-right axis never exceeded 50%. All treatments except methoxamine, an
α
1 adrenergic agonist, induced an abnormal left-right axis in association with other morphologic defects and growth retardation. However, there was no relationship between the severity or incidence of dysmorphology, nor growth retardation, and left-right abnormality, suggesting that: although the process that specifies lateral asymmetry is labile, it is independent of general growth and morphogenesis.
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