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Post-replicative initial expression of the cell fate regulator PAX6 during neuroectoderm formation [CUT&Tag]

ABSTRACT: Human neuroepithelial cells are the earliest neural progenitor cells (NPC) during brain development. The cell cycle is fundamental for cell proliferation and differentiation. How the cell cycle is linked to the differentiation process from embryonic stem cells (ESC) in blastocytes to neuroepithelial cells, however, is still unclear. In this study, using an in vitro ESC-to-NPC differentiation system and PAX6 as an NPC cell fate indicator, we discovered that the neural cell fate was transited, PAX6 expression exhibiting an incremental rise, during the G2 phase. For the mechanism, the loss of -401 bp to -450 bp from the transcription start site (TSS) of PAX6 efficiently blocked the cell cycle-dependent expression of PAX6. In addition, we found that using hydroxyurea to arrest the cell cycle of differentiating NPC could prevent NPC differentiation. Overall, this study reported the first scenario to link cell cycle and cell fate transition during early neurogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305658 | GEO | 2025/09/22

REPOSITORIES: GEO

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Project description:The coupling between cell-cycle exit and onset of differentiation is a common feature throughout the developing nervous system, but the mechanisms that link these processes are mostly unknown. Although the transcription factor Pax6 was implicated in both proliferation and differentiation of multiple regions within the CNS, its contribution to the transition between these successive states remains elusive. To gain insight into the role of Pax6 during the transition from proliferating progenitors to differentiating precursors, we investigated cell-cycle and transcriptomic changes occurring in Pax6- retinal progenitor cells (RPCs). Our analyses revealed a unique cell-cycle phenotype of the Pax6-deficient RPCs, which included a reduced number of cells in the S phase, an increased number of cells exiting the cell cycle, and delayed differentiation kinetics of Pax6- precursors. These alterations were accompanied by co-expression of factors that promote (Ccnd1, Ccnd2, Ccnd3) and inhibit (P27kip1 and P27kip2) the cell cycle. Further characterization of the changes in transcription profile of the Pax6-deficient RPCs revealed abrogated expression of multiple factors which are known to be involved in regulating proliferation of RPCs, including the transcription factors Vsx2, Nr2e1, Plagl1 and Hedgehog signaling. These findings provide novel insight into the molecular mechanism mediating the pleiotropic activity of Pax6 in RPCs. The results further suggest that rather than conveying a linear effect on RPCs, such as promoting their proliferation and inhibiting their differentiation, Pax6 regulates multiple transcriptional networks which function simultaneously, thereby conferring the capacity to proliferate, assume multiple cell fates and execute the differentiation program into retinal lineages. The data contains 3 control and 3 Pax6 negative samples representing biological repeats. Each sample was prepared from ~1.8 million cells taken from the distal retina of either E12 alpha-Cre or Pax6 floxed alpha-Cre animals. Distally located retinal progenitors expressing Cre and eGFP were separated using FACS.

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Post-replicative initial expression of the cell fate regulator PAX6 during neuroectoderm formation [CUT&Tag]

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