Practice question

Proliferative capacity varies markedly among differentiated tissues, with some lineages retaining ability to re-enter cycle while others become permanently postmitotic. Neurons illustrate irreversible exit: during corticogenesis, progenitor neuroepithelial cells divide, but committed neuroblasts after final mitosis migrate to cortical plate, extend axons and dendrites, and upregulate Cip/Kip inhibitors p27Kip1 and p57Kip2, maintaining retinoblastoma protein in hypophosphorylated state bound to E2F, repressing promoters of cyclins, PCNA, and MCM helicases through transcription factors REST/NRSF that silence neuronal progenitor genes and Polycomb complex PRC2 that deposits H3K27me3 repressive marks on cell cycle loci. Cytoskeletal architecture of mature neurons incompatible with mitotic rounding further enforces exit. In contrast, fibroblasts remain quiescent but can re-enter upon wound cytokines inducing cyclin D, and hepatocytes can re-enter after partial hepatectomy. Hence neuronal loss after injury is largely irreparable in mammals. This circuitry is highly conserved across eukaryotes, integrating growth factor signals, DNA damage surveillance, and developmental cues, and its disruption frequently underlies oncogenesis, providing targets for checkpoint inhibitors and cancer therapeutics.