Abstract
Outside of the neurogenic niches of the brain, postmitotic neurons have not been found to undergo efficient regeneration. We demonstrate that mouse Purkinje cells (PCs), which are born at midgestation and are crucial for development and function of cerebellar circuits, are rapidly and fully regenerated following their ablation at birth. New PCs are produced from immature FOXP2+ Purkinje cell precursors (iPCs) that are able to enter the cell cycle and support normal cerebellum development. The number of iPCs and their regenerative capacity, however, diminish soon after birth and consequently PCs are poorly replenished when ablated at postnatal day five. Nevertheless, the PC-depleted cerebella reach a normal size by increasing cell size, but scaling of neuron types is disrupted and cerebellar function is impaired. Our findings provide a new paradigm in the field of neuron regeneration by identifying a population of immature neurons that buffers against perinatal brain injury in a stage-dependent process.
Highlights
Most neurons in the brain are generated at specific developmental time points, and once a neuron becomes postmitotic regeneration following injury is limited, except for in two forebrain regions that maintain neurogenesis (Chaker et al, 2016)
We found that only 52.16 ± 21.84% of Purkinje cells (PCs) (n = 5 mice), identified by expression of CALB1, expressed TdT and diphtheria toxin receptor (DTR) at postnatal day (P) 1, and surprisingly the percentage and large variation remained similar at P5 and P30 (Figure 1—figure supplement 1)
When DT was injected at P1 into PC-DTR pups (P1-PC-DTR), most TdT+ PCs formed an ectopic layer below the PC layer (PCL) by 1 day post injection (Figure 1A–M)
Summary
Most neurons in the brain are generated at specific developmental time points, and once a neuron becomes postmitotic regeneration following injury is limited, except for in two forebrain regions that maintain neurogenesis (Chaker et al, 2016). Unlike the rest of the brain, which primarily develops in the womb, most of its cells appear within the first year of our lives (or first few weeks in mice) This makes it vulnerable to injury around the time of birth. We used to think that the brain could not replace damaged neurons, but when specific precursor cells in the cerebellum in the brains of newborn mice are removed, they are able to renew themselves. This is because specialized stem cells start to divide and produce the missing cells of the cerebellum. In this study we determined the regenerative potential of PCs in neonatal mice
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