Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease in humans. Transforming growth factor-␤ (TGF-␤) signaling plays an important role in PDAC progression, as indicated by the fact thatSmad4, which encodes a central signal mediator downstream from TGF-␤, is deleted or mutated in 55% and the type II TGF-␤ receptor (Tgfbr2) gene is altered in a smaller subset of human PDAC. Pancreas-specific Tgfbr2 knockout mice have been generated, alone or in the context of active Kras (Kras G12D) expression, using the Cre-loxP system driven by the endogenous Ptf1a (pancreatic transcription factor-1a) locus. Pancreas-selective Tgfbr2 knockout alone gave no discernable phenotype in 1.5 yr. Pancreas-specific Kras G12D activation alone essentially generated only intraepithelial neoplasia within 1 yr. In contrast, the Tgfbr2 knockout combined with Kras G12D expression developed well-differentiated PDAC with 100% penetrance and a median survival of 59 d. Heterozygous deletion of Tgfbr2 with Kras G12D expression also developed PDAC, which indicated a haploinsufficiency of TGF-␤ signaling in this genetic context. The clinical and histopathological manifestations of the combined Kras G12D expression and Tgfbr2 knockout mice recapitulated human PDAC. The data show that blockade of TGF-␤ signaling and activated Ras signaling cooperate to promote PDAC progression.[Keywords: Kras; pancreas-specific knockout; pancreatic ductal adenocarcinoma; Ptf1a; TGF-␤; type II TGF-␤ receptor] Supplemental material is available at http://www.genesdev.org. Pancreatic cancer is one of the leading causes of cancer death in many countries, and also is one of the most lethal diseases, with a <5% 5-yr survival rate (Warshaw and Fernandez-del Castillo 1992;Hezel et al. 2006;Jemal et al. 2006). Poor survival is likely because most of the patients are already at an unresectable stage when diagnosed. Moreover, even with a successful resection, most patients have recurrence within a year, and the tumors are resistant to all forms of conventional therapies. Since the most common form is pancreatic ductal adenocarcinoma (PDAC), to establish a good animal model that recapitulates aggressive full-blown human PDAC is of high importance for a better understanding of this disease, and for development of better means of early detection and treatment.Previous histological and molecular studies have suggested a model of disease evolution through a preinvasive state, termed pancreatic intraepithelial neoplasia (PanIN), along with accumulating specific genetic alterations (Hruban et al. 2001). An activating point mutation of the Kras proto-oncogene is found in PanIN lesions and with increasing frequency at later stages, and in >90% of

The vertebrate neural retina comprises six classes of neurons and one class of glial cells, all derived from a population of multipotent progenitors. There is little information on the molecular mechanisms governing the specification of cell type identity from multipotent progenitors in the developing retina. We report that Ptf1a, a basic-helix-loop-helix (bHLH) transcription factor, is transiently expressed by post-mitotic precursors in the developing mouse retina. Recombination-based lineage tracing analysis in vivo revealed that Ptf1a expression marks retinal precursors with competence to exclusively produce horizontal and amacrine neurons. Inactivation of Ptf1a leads to a fate-switch in these precursors that causes them to adopt a ganglion cell fate. This misspecification of neurons results in a complete loss of horizontal cells, a profound decrease of amacrine cells and an increase in ganglion cells. Furthermore, we identify Ptf1a as a primary downstream target for Foxn4, a forkhead transcription factor involved in the genesis of horizontal and amacrine neurons. These data, together with the previous findings on Foxn4, provide a model in which the Foxn4-Ptf1a pathway plays a central role in directing the differentiation of retinal progenitors towards horizontal and amacrine cell fates.

[Keywords: Organogenesis; pancreatic ␤ cells; Pdx1; MODY; Enhancer; cis-element; foregut differentiation] Supplemental material is available at http://www.genesdev.org.