Septo-temporal distribution and lineage progression of hippocampal neurogenesis in a primate (Callithrix jacchus) in comparison to mice.

Adult born neurons in the hippocampus show species-specific differences in their numbers, the pace of their maturation and their spatial distribution. Here, we present quantitative data on adult hippocampal neurogenesis in a New World primate, the common marmoset (Callithrix jacchus) that demonstrate parts of the lineage progression and age-related changes. Proliferation was largely (∼70%) restricted to stem cells or early progenitor cells, whilst the remainder of the cycling pool could be assigned almost exclusively to Tbr2+ intermediate precursor cells in both neonate and adult animals (20-122 months). Proliferating DCX+ neuroblasts were virtually absent in adults, although rare MCM2+/DCX+ co-expression revealed a small, persisting proliferative potential. Co-expression of DCX with calretinin was very limited in marmosets, suggesting that these markers label distinct maturational stages. In adult marmosets, numbers of MCM2+, Ki67+, and significantly Tbr2+, DCX+, and CR+ cells declined with age. The distributions of granule cells, proliferating cells and DCX+ young neurons along the hippocampal longitudinal axis were equal in marmosets and mice. In both species, a gradient along the hippocampal septo-temporal axis was apparent for DCX+ and resident granule cells. Both cell numbers are higher septally than temporally, whilst proliferating cells were evenly distributed along this axis. Relative to resident granule cells, however, the ratio of proliferating cells and DCX+ neurons remained constant in the septal, middle, and temporal hippocampus. In marmosets, the extended phase of the maturation of young neurons that characterizes primate hippocampal neurogenesis was due to the extension in a large CR+/DCX- cell population. This clear dissociation between DCX+ and CR+ young neurons has not been reported for other species and may therefore represent a key primate-specific feature of adult hippocampal neurogenesis.

Dissection of Drosophila MTF-1 reveals a domain for differential target gene activation upon copper overload vs. copper starvation.

Metal-responsive transcription factor-1 (MTF-1) is a zinc finger protein conserved from mammals to insects. It mediates protection against heavy metal load by activating the expression of metallothionein and other genes. In Drosophila, MTF-1 serves a dual function in that it not only helps to protect against heavy metal load but also induces the expression of Ctr1B, the gene for an intestinal copper importer, upon copper starvation. By dissecting Drosophila MTF-1 function, we have identified determinants for nuclear import and export, and characterized a phosphorylation site mutant (T127A) that differentially affects MTF-1 target genes. Further, by generating a series of fusion proteins with the heterologous DNA binding domain of Gal4 we identified a strong, constitutive activation domain in the central region of MTF-1 (aa 352-540). By contrast, an extended fusion protein that includes MTF-1's C-terminus (aa 352-791) is not active in standard conditions but induced by copper load. The paramount regulatory importance of the C-terminal part, that harbors a cysteine-rich "metallothionein-like" domain, was corroborated by different experiments. Transgenic flies expressing C-terminally truncated MTF-1 variants displayed high constitutive transcription of both, the genes for metallothioneins and the copper importer Ctr1B. The indiscriminate activation of these genes that are normally induced under opposite conditions of copper load and copper starvation manifested itself in a shortened lifespan, crippled wings, and female sterility.