Early Postnatal In Vivo Gliogenesis From Nestin-Lineage Progenitors Requires Cdk5

Abstract

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.

Acute oligodendrocyte loss with persistent white matter injury in a third trimester equivalent mouse model of fetal alcohol spectrum disorder

“…Reporter gene expression was selectively induced in postnatal nestin + SVZ progenitors by tamoxifen administration at P2, as previously described (Petrik et al 2013). Pups were then exposed to gradually increasing concentrations of EtOH within vapor chambers over the following 13 days from P3 to P15 (FIGURE 1).…”

“…At P50, n 5 4 EtOH exposed mice across 4 litters, and n 5 5 air exposed mice across 4 litters were transcardially perfused with PBS containing 0.1% procaine and 2 U/ml heparin, followed with perfusion Reporter gene expression was selectively induced in postnatal nestin 1 SVZ progenitors by tamoxifen administration at P2, as previously described (Petrik et al, 2013). Pups were then exposed to gradually increasing concentrations of EtOH within vapor chambers over the following 13 days from P3 to P15 (Figure 1).…”

The Role of Cdk5 in Alzheimer’s Disease

“…Cdk5 activity is essential for a variety of neuronal functions in both developing and mature neurons [12]. Regulated Cdk5 is important for normal development of the CNS by phosphorylating the specific serine or threonine site of numerous substrate proteins closely associated with cortex layer formation, neurotransmission, synaptic growth, stress-enhanced memory consolidation, neuronal migration and differentiation [15], neurite outgrowth [16], associative learning and long-term behavioral changes, gliogenesis [17], as well as normal cerebellar development and functions [18,19]. More recently, it is demonstrated that sumoylation (small ubiquitin-related modifier (SUMO)) of p35 elevates the activity of the p35/Cdk5 complex [20].…”

Transcriptional analysis of glial cell differentiation in the postnatal murine spinal cord

“…Production and development of astrocytes is also suggested as a major event in the early postnatal development (Bushong et al, 2004; Ge et al, 2012; Petrik et al, 2013). The number of immunopositive cells for GFAP showed no significant differences between the time‐points.…”