We have generated a mouse bearing a null allele of the gene encoding basic helix-loop-helix (bHLH) protein p48, the cell-specific DNA-binding subunit of hetero-oligomeric transcription factor PTF1 that directs the expression of genes in the exocrine pancreas. The null mutation, which establishes a lethal condition shortly after birth, leads to a complete absence of exocrine pancreatic tissue and its specific products, indicating that p48 is required for differentiation and/or proliferation of the exocrine cell lineage. p48 is so far the only developmental regulator known to be required exclusively for committing cells to an exocrine fate. The hormone secreting cells of all four endocrine lineages are present in the mesentery that normally harbors the pancreatic organ until day 16 of gestation. Toward the end of embryonic life, cells expressing endocrine functions are no longer detected at their original location but are now found to colonize the spleen, where they persist in a functional state until postnatal death of the organism occurs. These findings suggest that the presence of the exocrine pancreas is required for the correct spatial assembly of the endocrine pancreas and that, in its absence, endocrine cells are directed by default to the spleen, a site that, in some reptiles, harbors part of this particular cellular compartment.[Key Words: Genetics; gene inactivation; transcription factor; bHLH protein; morphogenesis; pancreas; mouse]Received June 4, 1998; revised version accepted September 30, 1998. The mammalian pancreas develops by fusion of dorsal and ventral primordia that originate from an evagination of the foregut early during development. Both the endocrine and exocrine portions of the gland differentiate from a common pool of endodermal progenitor cells (Pictet and Rutter 1972;Le Douarin 1988). The exocrine acinar cells secrete digestive enzymes into the gastrointestinal tract, while the four types of endocrine islet cells are specialized for the synthesis of different hormones. Islet cell-specific differentiation has been studied extensively in rodents and found to require the action of genes encoding homeotic proteins Pdx-1 and Isl-1. Pdx-1 (previously termed Ipf-1), the ortholog of the XlHbox8 protein of the frog (Wright et al. 1988), is transiently expressed in all pancreatic cells as well as in the epithelial layer of the duodenal mucosa during embryogenesis (Leonard et al. 1993;Ohlsson et al. 1993;Jonsson et al. 1994;Miller et al. 1994). As development proceeds, Pdx-1 becomes progressively confined to endocrine ␤ cells, where it plays a critical role in the transcriptional regulation of the insulin gene (Ohlsson 1993;Guz 1995). Mice carrying a null allele of the gene encoding this protein do not form a pancreatic gland even though the primordia are formed and the dorsal organ undergoes some limited proliferation (Jonsson 1994;Offield 1996). In addition, the duodenum displays a local absence of epithelial lining (Offield 1996). These observations support a model by which Pdx-1 is expressed ...

We report the isolation of cDNA for the p48 DNA‐binding subunit of the heterooligomeric transcription factor PTF1. A sequence analysis of the cDNA demonstrates that p48 is a new member of the family of basic helix‐loop‐helix (bHLH) transcription factors. The p48 bHLH domain shows striking amino acid sequence similarity with the bHLH domain of proteins that act as developmental regulators, including the twist gene product, myogenic factors and proteins involved in hematopoietic differentiation. We show that reduced p48 synthesis correlates with a diminished expression of genes encoding exocrine pancreas‐specific functions. The synthesis of p48 mRNAs, and therefore also the protein, is restricted to cells of the exocrine pancreas in the adult and to the pancreatic primordium in the embryo. Thus the pancreas‐specific DNA‐binding activity of PTF1 originates from the synthesis of at least one cell‐specific component rather than from a cell‐specific assembly of more widely distributed proteins.

the spindle pole body during mitosis, from where it is presumed that the 1919 Route de Mende, 34293 Montpellier signal for septum formation is delivered. Cdc11 mutants are defective in Cedex 5, France.SIN signaling, but the role of cdc11 in the pathway has remained enigmatic.

The fission yeast septation initiation network, or SIN, is a signal transduction network that is required for septum formation in Schizosaccharomyces pombe. Its activity is tightly regulated through the cell cycle, to ensure proper co-ordination of mitosis and cytokinesis. SIN signalling requires three protein kinases for its function and is mediated by a ras-superfamily GTPase. We discuss the elements of the SIN and how they are regulated.

Mitotic exit in