In line with this, p27 has been shown to promote the differentiation of fetal cortical NPCs through its ability to stabilize TF neurogenin 2 ( Nguyen et al, 2006) or to repress Sox2 gene expression in embryonic stem (ES) and pituitary cells ( Li et al, 2012 Moncho-Amor et al, 2021). Interestingly, CKI p27 plays roles beyond the control of cell cycle core machinery through cyclinE/CDK2 inhibition (Lim and Kaldis, 2015 Defoe et al., 2020). Reported analyses at the single cell level in the developing CNS have indicated that fetal progenitors without p27 undergo one or two extra rounds of cell division before they stop cycling and differentiate, but the underlying mechanism for such a complex cell behavior has not been elucidated ( Durand et al, 1998 Raff, 2007 Defoe et al., 2020). Cdkn1b mutant mice (p27KO) are larger in size and exhibit hyperplasia in all organs ( Fero et al, 1996 Kiyokawa et al, 1996 Nakayama et al, 1996) suggesting that it plays a role in timing the onset of differentiation in many cell lineages.
Previous analyses have shown that p21 regulates self-renewal of subependymal NSCs ( Kippin et al, 2005 Marqués-Torrejón et al, 2013 Porlan et al, 2014) whereas p27 (encoded by the Cdkn1b gene) appears to act as a cell cycle inhibitor of adult NPCs ( Doetsch et al, 2002 Gil-Perotín et al, 2011). Members of the INK4 family p16 Ink4a, p15 Ink4b, p18 Ink4c, and p19 Ink4d inhibit early G1 CDKs 4 and 6, whereas the more promiscuous members of the Cip/Kip family p21 Cip1, p27 kip1, and p57 Kip2 can interact with all cyclin-CDK complexes throughout the cell cycle ( Besson et al, 2008). Two families of cyclin-dependent kinase inhibitors (CKIs) inhibit cell cycle progression by blocking the activity of cyclin/cyclin-dependent kinases (CDK) complexes. Cell fate decisions along a multistep biological process are dictated and sustained by master TFs, chromatin regulators, and associated networks, but these programs need to act in concert with the regulation of cell cycling and cell cycle exit, a coordination that is still poorly understood ( Hardwick et al, 2015). NPCs can also give rise to a small population of oligodendroglial progenitor cells (OPCs) that integrate into the corpus callosum (CC) and differentiate into oligodendrocytes ( Menn et al, 2006), as well as to some striatal and CC astrocytes ( Sohn et al., 2015). These NPCs rapidly divide 3-4 times before they give rise to neuroblasts which themselves divide at least once while migrating to the olfactory bulb (OB) where they exit the cell cycle to fully differentiate as interneurons ( Ponti et al, 2013 Obernier and Alvarez-Buylla, 2019). In the subependymal zone (SEZ) of the adult mouse brain, astrocyte-like neural stem cells (NSCs) generate transit-amplifying neural progenitor cells (NPCs) that express the stemness-related transcription factor (TF) SOX2 (Sry-related HMG box 2) and a priming combination of neuron and oligodendroglia fate-specifying bHLH TFs, such as ASCL1 (Achaete-scute homologue 1 also known as MASH1), DLX2 (Distal-Less Homeobox 2) or OLIG2 (Oligodendrocyte Transcription Factor 2) ( Gotz et al., 2016 Obernier and Alvarez-Buylla, 2019). Mammalian stem and progenitor cell activities are hierarchically organized to produce appropriate numbers of specialized cell types during development and adult tissue renewal. In vivo, p27 is also required for the regulation of the proper level of SOX2 necessary for neuroblasts and oligodendroglial progenitor cells to timely exit cell cycle in a lineage-dependent manner.
Our data reveal both direct association of p27 with regulatory sequences in the three genes and an additional hierarchical relationship where p27 repression of the Sox2 gene leads to reduced levels of SOX2-downstream targets Olig2 and Ascl1. Contrasting gene expression with chromatin accessibility, we find that p27 is coincidentally necessary to globally repress many genes involved in the transit from multipotentiality to differentiation, including those coding for neural progenitor transcription factors SOX2, OLIG2, and ASCL1.
At the cell level, we show that p27 restricts residual cyclin-dependent kinase activity after mitogen withdrawal to antagonize cycling, but it is not essential for cell cycle exit. Because cyclin-dependent kinase inhibitor p27 reportedly regulates proliferation of neural progenitor cells in the subependymal neurogenic niche of the adult mouse brain, but can also have effects on gene expression, we decided to molecularly analyze its role in adult neurogenesis and oligodendrogenesis. Cell differentiation involves profound changes in global gene expression that often have to occur in coordination with cell cycle exit.
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