p27^Kip1participates in the regulation of endoreplication in differentiating chick retinal ganglion cells

Abstract

Nuclear DNA duplication in the absence of cell division (i.e. endoreplication) leads to somatic polyploidy in eukaryotic cells. In contrast to some invertebrate neurons, whose nuclei may contain up to 200,000-fold the normal haploid DNA amount (C), polyploid neurons in higher vertebrates show only 4C DNA content. To explore the mechanism that prevents extra rounds of DNA synthesis in these latter cells we focused on the chick retina, where a population of tetraploid retinal ganglion cells (RGCs) has been described. We show that differentiating chick RGCs that express the neurotrophic receptors p75 and TrkB while lacking retinoblastoma protein, a feature of tetraploid RGCs, also express p27 Kip1 . Two different short hairpin RNAs (shRNA) that significantly downregulate p27 Kip1 expression facilitated DNA synthesis and increased ploidy in isolated chick RGCs. Moreover, this forced DNA synthesis could not be prevented by Cdk4/6 inhibition, thus suggesting that it is triggered by a mechanism similar to endoreplication. In contrast, p27 Kip1 deficiency in mouse RGCs does not lead to increased ploidy despite previous observations have shown ectopic DNA synthesis in RGCs from p27 Kip1¡/¡ mice. This suggests that a differential mechanism is used for the regulation of neuronal endoreplication in mammalian versus avian RGCs.

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Cell Cycle Re-entry in the Nervous System: From Polyploidy to Neurodegeneration

“…Modern genetic approaches investigating potential cell cycle re-entry in vertebrate brains began taking shape in the early 2000’s. In recent years, observations of bona fide polyploidy in neurons of the retinal ganglion of the chicken and mouse, cerebral cortex of the rat and neocortex of the mouse have been made using modern flow cytometry and high resolution imaging techniques ( Morillo et al, 2010 ; López-Sánchez and Frade, 2013 ; Ovejero-Benito and Frade, 2015 ; Martin et al, 2017 ; Jungas et al, 2020 ). Work from the Frade lab has shown that the neurons of the retinal ganglion become tetraploid in an E2F-dependent manner.…”

Strand-specific CpG hemimethylation, a novel epigenetic modification functional for genomic imprinting

“…The mechanism leading to neuronal tetraploidy depends on the activation of the neurotrophin receptor p75 ( 11 , 12 ), which induces the activation of p38 MAPK and the subsequent phosphorylation of E2F4 ( 14 ), a key regulator of the cell cycle. After DNA replication, Cdk1inactivation prevents differentiating 4C neurons from entering mitosis ( 15 ), while p27 Kip1 expression in these cells avoids further rounds of endoreplication ( 16 ). Somatic 4C neurons show extensive dendritic arbors and enlarged cell bodies ( 12 ), express the immediate early genes Erg-1 and c-Fos ( 11 ), known to respond to neuronal activity ( 17 , 18 ), and constitute specific neuronal populations that innervate defined target areas ( 12 ), thus indicating that 4C neurons are fully functional.…”