SUMMARYOne major unresolved question in the field of pancreas biology is whether ductal cells have the ability to generate insulinproducing b-cells. Conclusive examination of this question has been limited by the lack of appropriate tools to efficiently and specifically label ductal cells in vivo. We generated Sox9CreER T2 mice, which, during adulthood, allow for labeling of an average of 70% of pancreatic ductal cells, including terminal duct/centroacinar cells. Fate-mapping studies of the Sox9 + domain revealed endocrine and acinar cell neogenesis from Sox9 + cells throughout embryogenesis. Very small numbers of non-b endocrine cells continue to arise from Sox9 + cells in early postnatal life, but no endocrine or acinar cell neogenesis from Sox9 + cells occurs during adulthood. In the adult pancreas, pancreatic injury by partial duct ligation (PDL) has been suggested to induce b-cell regeneration from a transient Ngn3 + endocrine progenitor cell population. Here, we identify ductal cells as a cell of origin for PDL-induced Ngn3 + cells, but fail to observe b-cell neogenesis from duct-derived cells. Therefore, although PDL leads to activation of Ngn3 expression in ducts, PDL does not induce appropriate cues to allow for completion of the entire b-cell neogenesis program. In conclusion, although endocrine cells arise from the Sox9 + ductal domain throughout embryogenesis and the early postnatal period, Sox9 + ductal cells of the adult pancreas no longer give rise to endocrine cells under both normal conditions and in response to PDL.

The protease inhibitor alpha 1-antichymotrypsin and the lipid transport protein apolipoprotein E (apoE) are intimately associated with the 42-amino-acid beta-peptide (A beta) in the filamentous amyloid deposits of Alzheimer's disease. We report here that these two amyloid-associated proteins serve a strong stimulatory role in the polymerization of A beta into amyloid filaments. Addition of either alpha 1-anti-chymotrypsin or apoE to the A beta peptide promoted a 10- to 20-fold increase in filament formation, with apoE-4, the isoform recently linked to the development of late-onset Alzheimer's disease, showing the highest catalytic activity. These and other experiments suggest that Alzheimer amyloid deposits arise when A beta is induced to form filaments by amyloid-promoting factors (pathological chaperones) expressed in certain brain regions.

Unlike sensory thalamus, studies on the functional organization of midline and intralaminar nuclei are scarce, and this has hampered the establishment of conceptual models on the function of this brain region. We have investigated the functional organization of the paraventricular nucleus of the thalamus (PVT), a midline thalamic structure increasingly being recognized as a critical node in the control of diverse processes such as arousal, stress, emotional memory and motivation, in mice. We identify two major classes of PVT neurons – termed Type I and Type II – that differ in terms of gene expression, anatomy and function. In addition, we demonstrate that Type II neurons belong to a previously neglected class of PVT neurons that conveys arousal-related information to corticothalamic neurons of the infralimbic cortex. Our results uncover the existence of an arousal-modulated thalamo-corticothalamic loop that links the PVT and the ventromedial prefrontal cortex.

Mutations in two related genes, presenilin 1 and 2, account for most early-onset familial Alzheimer's disease. Although structural features indicate that the presenilins are membrane proteins, their function(s) is unknown. We have localized the presenilins to the nuclear membrane, its associated interphase kinetochores, and the centrosomes-all subcellular structures involved in cell cycle regulation and mitosis. The colocalization of the presenilins with kinetochores on the nucleoplasmic surface of the inner nuclear membrane, together with other results, suggests that they may play a role in chromosome organization and segregation, perhaps as kinetochore binding proteins/receptors. We discuss a pathogenic pathway for familial Alzheimer's disease in which defective presenilin function causes chromosome missegregation during mitosis, resulting in apoptosis and/or trisomy 21 mosaicism.