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Embryonic cells are expected to possess high growth/differentiation potential, required for organ morphogenesis and expansion during development. However, little is known about the intrinsic properties of embryonic epithelial cells due to difficulties in their isolation and cultivation. We report here that pure keratinocyte populations from E15.5 mouse embryos commit irreversibly to differentiation much earlier than newborn cells. Notch signaling, which promotes keratinocyte differentiation, is upregulated in embryonic keratinocyte and epidermis, and elevated caspase 3 expression, which we identify as a transcriptional Notch1 target, accounts in part for the high commitment of embryonic keratinocytes to terminal differentiation. In vivo, lack of caspase 3 results in increased proliferation and decreased differentiation of interfollicular embryonic keratinocytes, together with decreased activation of PKC-delta, a caspase 3 substrate which functions as a positive regulator of keratinocyte differentiation. Thus, a Notch1-caspase 3 regulatory mechanism underlies the intrinsically high commitment of embryonic keratinocytes to terminal differentiation.

Gains of 1q21-q23 have been associated with metastasis and chemotherapy response, particularly in bladder cancer, hepatocellular carcinomas and sarcomas. By positional cloning of ampli®ed genes by yeast arti®cial chromosome-mediated cDNA capture using magnetic beads, we have identi®ed three candidate genes (COAS1, -2 and -3) in the ampli®ed region in sarcomas. COAS1 and -2 showed higher ampli®cation levels than COAS3. Most notably, ampli®cation was very common in osteosarcomas, where in particular COAS2 was highly expressed. COAS1 has multiple repeats and shows no homology to previously described genes, whereas COAS2 is a novel member of the cyclosporin-binding peptidylprolyl isomerase family, very similar to cyclophilin A. COAS2 was overexpressed almost exclusively in aggressive metastatic or chemotherapy resistant tumours. Although COAS2 was generally more ampli®ed than COAS1, it was not expressed in well-di erentiated liposarcomas, where ampli®cation of this region is very common. All three genes were found to be ampli®ed and over-expressed also in breast carcinomas. The complex nature of the 1q21-23 amplicons and close proximity of the genes make unequivocal determination of the gene responsible di cult. Quite likely, the di erent genes may give selective advantages to di erent subsets of tumours.