Early postnatal in vivo gliogenesis from nestin-lineage progenitors requires Cdk5

The early postnatal period is a unique time of brain development, as diminishing amounts of neurogenesis coexist with waves of gliogenesis. Understanding the molecular regulation of early postnatal gliogenesis may provide clues to normal and pathological embryonic brain ontogeny, particularly in regards to the development of astrocytes and oligodendrocytes. Cyclin dependent kinase 5 (Cdk5) contributes to neuronal migration and cell cycle control during embryogenesis, and to the differentiation of neurons and oligodendrocytes during adulthood. However, Cdk5’s function in the postnatal period and within discrete progenitor lineages is unknown. Therefore, we selectively removed Cdk5 from nestin-expressing cells and their progeny by giving transgenic mice (nestin-CreERT2/R26R-YFP/CDK5flox/flox [iCdk5] and nestin-CreERT2/R26R-YFP/CDK5wt/wt [WT]) tamoxifen during postnatal (P) days P2-P 4 or P7-P 9, and quantified and phenotyped recombined (YFP+) cells at P14 and P21. When Cdk5 gene deletion was induced in nestin-expressing cells and their progeny during the wave of cortical and hippocampal gliogenesis (P2-P4), significantly fewer YFP+ cells were evident in the cortex, corpus callosum, and hippocampus. Phenotypic analysis revealed the cortical decrease was due to fewer YFP+ astrocytes and oligodendrocytes, with a slightly earlier influence seen in oligodendrocytes vs. astrocytes. This effect on cortical gliogenesis was accompanied by a decrease in YFP+ proliferative cells, but not increased cell death. The role of Cdk5 in gliogenesis appeared specific to the early postnatal period, as induction of recombination at a later postnatal period (P7-P9) resulted in no change YFP+ cell number in the cortex or hippocampus. Thus, glial cells that originate from nestin-expressing cells and their progeny require Cdk5 for proper development during the early postnatal period

Early postnatal in vivo gliogenesis from nestin-lineage progenitors requires Cdk5

The early postnatal period is a unique time of brain development, as diminishing amounts of neurogenesis coexist with waves of gliogenesis. Understanding the molecular regulation of early postnatal gliogenesis may provide clues to normal and pathological embryonic brain ontogeny, particularly in regards to the development of astrocytes and oligodendrocytes. Cyclin dependent kinase 5 (Cdk5) contributes to neuronal migration and cell cycle control during embryogenesis, and to the differentiation of neurons and oligodendrocytes during adulthood. However, Cdk5’s function in the postnatal period and within discrete progenitor lineages is unknown. Therefore, we selectively removed Cdk5 from nestin-expressing cells and their progeny by giving transgenic mice (nestin-CreERT2/R26R-YFP/CDK5flox/flox [iCdk5] and nestin-CreERT2/R26R-YFP/CDK5wt/wt [WT]) tamoxifen during postnatal (P) days P2-P 4 or P7-P 9, and quantified and phenotyped recombined (YFP+) cells at P14 and P21. When Cdk5 gene deletion was induced in nestin-expressing cells and their progeny during the wave of cortical and hippocampal gliogenesis (P2-P4), significantly fewer YFP+ cells were evident in the cortex, corpus callosum, and hippocampus. Phenotypic analysis revealed the cortical decrease was due to fewer YFP+ astrocytes and oligodendrocytes, with a slightly earlier influence seen in oligodendrocytes vs. astrocytes. This effect on cortical gliogenesis was accompanied by a decrease in YFP+ proliferative cells, but not increased cell death. The role of Cdk5 in gliogenesis appeared specific to the early postnatal period, as induction of recombination at a later postnatal period (P7-P9) resulted in no change YFP+ cell number in the cortex or hippocampus. Thus, glial cells that originate from nestin-expressing cells and their progeny require Cdk5 for proper development during the early postnatal period

Inducible deletion of Cdk5 in nestin-lineage cells results in fewer YFP+ cells in the hippocampus and corpus callosum.

<p>(<b>A</b>) Paradigm of Tam administration. Representative images of the brain at P14 (<b>B</b>, <b>C</b>) and P21 (<b>D</b>, <b>E</b>) at P14 in WT (top) and iCdk5 littermates (bottom) highlighting cortex, corpus callosum (cc), and hippocampus with stratum oriens (Or), CA1, stratum radiatum (Rad) and molecular layer (Mol, s.b.=100 µm). Total number of YFP+ cells in Or (<b>F</b>), Rad (<b>G</b>; inset shows typical YFP+ Rad cell at P14, s.b.=10 µm), and cc (<b>H</b>).</p

Inducible deletion of Cdk5 in nestin-lineage cells via Tam P7-P9 does not change YFP+ cell number in hippocampus or cortex.

<p>(<b>A</b>) Paradigm for Tam administration. Representative images of YFP-stained hippocampi from P14 (<b>B</b>, <b>C</b>) and P21 (<b>D</b>, <b>E</b>) show YFP+ cells in corpus callosum (cc), stratum oriens (Or) and <i>radiatum</i> (Rad) in WT (top) and iCdk5 littermates (bottom; scale bar, s.b.=100 µm). Stereological quantification of YFP+ cells in the Or (<b>F</b>), Rad (<b>G</b>), cortex (<b>H</b>) and cc (<b>I</b>).</p

56Fe particle exposure results in a long-lasting increase in a cellular index of genomic instability and transiently suppresses adult hippocampal neurogenesis in vivo

The high-LET HZE particles from galactic cosmic radiation pose tremendous health risks to astronauts, as they may incur sub-threshold brain injury or maladaptations that may lead to cognitive impairment. The health effects of HZE particles are difficult to predict and unfeasible to prevent. This underscores the importance of estimating radiation risks to the central nervous system as a whole as well as to specific brain regions like the hippocampus, which is central to learning and memory. Given that neurogenesis in the hippocampus has been linked to learning and memory, we investigated the response and recovery of neurogenesis and neural stem cells in the adult mouse hippocampal dentate gyrus after HZE particle exposure using two nestin transgenic reporter mouse lines to label and track radial glia stem cells (Nestin-GFP and Nestin-CreER(T2)/R26R:YFP mice, respectively). Mice were subjected to (56)Fe particle exposure (0 or 1 Gy, at either 300 or 1000 MeV/n) and brains were harvested at early (24h), intermediate (7d), and/or long time points (2–3mo) post-irradiation. (56)Fe particle exposure resulted in a robust increase in 53BP1+ foci at both the intermediate and long time points post-irradiation, suggesting long-term genomic instability in the brain. However, (56)Fe particle exposure only produced a transient decrease in immature neuron number at the intermediate time point, with no significant decrease at the long time point post-irradiation. (56)Fe particle exposure similarly produced a transient decrease in dividing progenitors, with fewer progenitors labeled at the early time point but equal number labeled at the intermediate time point, suggesting a recovery of neurogenesis. Notably, (56)Fe particle exposure did not change the total number of nestin-expressing neural stem cells. These results highlight that despite the persistence of an index of genomic instability, (56)Fe particle-induced deficits in adult hippocampal neurogenesis may be transient. These data support the regenerative capacity of the adult SGZ after HZE particle exposure and encourage additional inquiry into the relationship between radial glia stem cells and cognitive function after HZE particle exposure