During development in the cellular slime mould Dictyostelium discoideum starved amoebae aggregate to form multicellular structures that display a simple antero-posterior pattern: prestalk cells occupy the front 20% of the aggregate, and prespore cells occupy the remainder. We have attempted to elucidate the nature of the mechanism regulating the proportions of the two cell types by examining the factors that influence the pathway of differentiation of amoebae in vitro. Amoebae of D. discoideum strain V12 M2 form stalk cells efficiently in appropriate conditions and 'sporogenous' derivatives produce spores as well as stalk cells. Mature spores are formed in a medium containing only cyclic AMP and salts, whereas formation of stalk cells requires, in addition, a low molecular weight hydrophobic factor (DIF). Recent observations have led us to propose that DIF is a morphogen responsible for activating stalk cell differentiation. Here we present evidence that ammonia is a second morphogen, that acts antagonistically to DIF, and that the choice of differentiation pathway is mediated by intracellular pH.
Expression of Wnt-4, a member of the Wnt gene family, is induced during early pregnancy in the mouse mammary gland. To investigate the function of Wnt-4, we used a recombinant retrovirus to constitutively express the gene in transplanted mammary epithelium grown in virgin animals. In fully grown glands, Wnt-4 expression resulted in ducts that were more highly branched than normal and caused some premature alveolar development. These changes resembled those seen during pregnancy, suggesting that endogenous Wnt-4 expression may regulate epithelial branching in early pregnancy. The modified growth pattern induced by Wnt-4 expression was similar to that induced by Wnt-1, one of the members of the Wnt gene family activated by mouse mammary tumour virus. As Wnt-1 is not normally expressed in the mammary gland, it may exert its effect on the mammary gland by activating a developmental pathway normally regulated by Wnt-4.
To maintain genomic stability, despite constant exposure to agents that damage DNA, eukaryotic cells have developed elaborate and highly conserved pathways of DNA damage sensing, signalling and repair. In this review, we concentrate mainly on what we know about DNA damage sensing with particular reference to Lcd1p, a yeast protein that functions early in DNA damage signalling, and MDC1 (mediator of DNA damage checkpoint 1), a recently identified human protein that may be involved in recruiting the MRE11 complex to radiation-induced nuclear foci. We describe a model for the DNA damage response in which factors are recruited sequentially to sites of DNA damage to form complexes that can amplify the original signal and propagate it to the multitude of response pathways necessary for genome stability.
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