Restriction of Late Cerebral Cortical Progenitors to an Upper-Layer Fate

AbstractEarly in development, neural progenitors in cerebral cortex normally produce neurons of several layers during successive cell divisions. The laminar fate of their daughters depends on environmental cues encountered just before mitosis. At the close of neurogenesis, however, cortical progenitors normally produce neurons destined only for the upper layers. To assess the developmental potential of these cells, upper-layer progenitors were transplanted into the cerebral cortex of younger hosts, in which deep-layer neurons were being generated. These studies reveal that late cortical progenitors are not competent to generate deep-layer neurons and are instead restricted to producing the upper layers

Hepatocytes express nerve growth factor during liver injury: evidence for paracrine regulation of hepatic stellate cell apoptosis

A key feature of recovery from liver fibrosis is hepatic stellate cell (HSC) apoptosis, which serves the dual function of removing the major source of neomatrix and tissue inhibitors of metalloproteinases thereby facilitating matrix degradation. The mechanisms regulating HSC apoptosis remain undefined but may include the interaction of nerve growth factor (NGF) with its receptor, p75, on HSC. In this study, by TaqMan polymerase chain reaction in situ hybridization and immunohistochemistry, we demonstrate that NGF is expressed by hepatocytes during fibrotic injury. Peak hepatocyte expression of NGF (48 hours after CCl4 injection) coincides with maximal rate of apoptosis of HSC by terminal dUTP nick-end labeling staining. Addition of recombinant NGF to HSC in tissue culture causes a dose-dependent increase in apoptosis. NGF regulates nuclear factor (NF)-?B activity, reducing p50/p65 binding detected by electromobility shift assay and reduced NF-?B CAT reporter activities from both basal unstimulated levels and after NF-?B induction by tumor necrosis factor. In each case, a relative reduction in NF-?B binding was associated with a significant increase in caspase 3 activity. These data provide evidence that NGF is expressed during fibrotic liver injury and may regulate number of activated HSCs via induction of apoptosis

Secreted sulfatases Sulf1 and Sulf2 have overlapping yet essential roles in mouse neonatal survival.

BackgroundHeparan sulfate proteoglycans (HSPGs) use highly sulfated polysaccharide side-chains to interact with several key growth factors and morphogens, thereby regulating their accessibility and biological activity. Various sulfotransferases and sulfatases with differing specificities control the pattern of HSPG sulfation, which is functionally critical. Among these enzymes in the mouse are two secreted 6-O-endosulfatases, Sulf1 and Sulf2, which modify HSPGs in the extracellular matrix and on the cell surface. The roles of Sulf1 and Sulf2 during normal development are not well understood.Methods/resultsTo investigate the importance of Sulf1 and Sulf2 for embryonic development, we generated mice genetically deficient in these genes and assessed the phenotypes of the resulting secreted sulfatase-deficient mice. Surprisingly, despite the established crucial role of HSPG interactions during development, neither Sulf1- nor Sulf2-deficient mice showed significant developmental flaws. In contrast, mice deficient in both Sulf1and Sulf2 exhibited highly penetrant neonatal lethality. Loss of viability was associated with multiple, although subtle, developmental defects, including skeletal and renal abnormalities.ConclusionsThese results show that Sulf1 and Sulf2 play overlapping yet critical roles in mouse development and are redundant and essential for neonatal survival