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 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

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