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DNA replication licensing factor MCM2 (EC (Minichromosome maintenance protein 2 homolog) (Nuclear protein BM28) [BM28] [CCNL1] [CDCL1] [KIAA0030]


Trophoblast type-specific expression of senescence markers in the human placenta.

Cell senescence is irreversible cell cycle arrest. The human placenta is a unique organ that grows and matures during pregnancy until 40 weeks of gestation. However, the role of senescence in placental villi, particularly in the two types of trophoblast, has not yet been elucidated in detail. Therefore, we herein investigated the expression of cell senescence-related markers in trophoblast. Seventy normal placental tissues were used. The expression of senescence-associated beta-galactosidase (SA-β-gal), cell senescence-related markers (p16, p21, and promyelocytic leukemia; PML), and a growth marker (MCM2) was immunohistochemically examined. The expression of these markers in BeWo cells before and after cell fusion using forskolin was also investigated. The expression of MCM2 is detected in cytotrophoblast (CT). The expression of SA-β-gal in CT is strong in the first and second trimesters, but weaker in the third trimester. Syncytiotrophoblast (ST) are negative in the first and second trimesters, but become positive in the third trimester. The immunohistochemical expression of p16, p21, and PML is stronger in CT than in ST throughout pregnancy. Furthermore, the expression of these markers in ST significantly increases as pregnancy advances. The expression of SA-β-gal, PML, and p21 in BeWo cells is stronger after than before cell fusion. The proliferation and senescence of CT occurred in early to mid-pregnancy in association with syncytial fusion, while senescence was observed in ST in late pregnancy. This coordinated trophoblastic senescence may be essential for maintaining placental function.

MeSH Terms

  • Biomarkers
  • Cellular Senescence
  • Female
  • Humans
  • Pregnancy
  • Trophoblasts


  • Cell senescence
  • Cytotrophoblast
  • Placenta
  • Senescence-associated beta-galactosidase
  • Syncytiotrophoblast

Changes in MCM2-7 proteins at senescence.

Cellular aging is characterized by the loss of DNA replication capability and is mainly brought about by various changes in chromatin structure. Here, we examined changes in MCM2-7 proteins, which act as a replicative DNA helicase, during aging of human WI38 fibroblasts at the single-cell level. We used nuclear accumulation of p21 as a marker of senescent cells, and examined changes in MCM2-7 by western blot analysis. First, we found that senescent cells are enriched for cells with a DNA content higher than 4N. Second, the levels of MCM2, MCM3, MCM4 and MCM6 proteins decreased in senescent cells. Third, cytoplasmic localization of MCM2 and MCM7 was observed in senescent cells, from an analysis of MCM2-7 except for MCM5. Consistent with this finding, fragmented MCM2 was predominant in these cells. These age-dependent changes in MCM2-7, a protein complex that directly affects cellular DNA replication, may play a critical role in cellular senescence.

MeSH Terms

  • Cell Cycle Proteins
  • Cellular Senescence
  • DNA Replication
  • Gene Expression Regulation
  • Humans
  • Minichromosome Maintenance Complex Component 2
  • Minichromosome Maintenance Complex Component 3
  • Minichromosome Maintenance Complex Component 4
  • Minichromosome Maintenance Complex Component 6
  • Minichromosome Maintenance Complex Component 7
  • Multiprotein Complexes
  • Single-Cell Analysis
  • p21-Activated Kinases


  • DNA content
  • MCM2–7 proteins
  • cellular aging
  • cellular localization
  • protein degradation

Evaluation of Nestin Expression in the Developing and Adult Mouse Inner Ear.

Adult stem cells are undifferentiated cells with the capacity to proliferate and form mature tissue-specific cell types. Nestin is an intermediate filament protein used to identify cells with stem cell characteristics. Its expression has been observed in a population of cells in developing and adult cochleae. In vitro studies using rodent cochlear tissue have documented the potential of nestin-expressing cells to proliferate and form hair and supporting cells. In this study, nestin coupled to green fluorescent protein (GFP) transgenic mice were used to provide a more complete characterization of the spatial and temporal expression of nestin in the inner ear, from organogenesis to adulthood. During development, nestin is expressed in the spiral ganglion cell region and in multiple cell types in the organ of Corti, including nascent hair and supporting cells. In adulthood, its expression is reduced but persists in the spiral ganglion, in a cell population medial to and below the inner hair cells, and in Deiters' cells in the cochlear apex. Moreover, nestin-expressing cells can proliferate in restricted regions of the inner ear during development shown by coexpression with Ki67 and MCM2 and by 5-ethynyl-2'-deoxyuridine incorporation. Results suggest that nestin may label progenitor cells during inner ear development and may not be a stem cell marker in the mature organ of Corti; however, nestin-positive cells in the spiral ganglion exhibit some stem cell characteristics. Future studies are necessary to determine if these cells possess any latent stem cell-like qualities that may be targeted as a regenerative approach to treat neuronal forms of hearing loss.

MeSH Terms

  • Aging
  • Animals
  • Animals, Newborn
  • Biomarkers
  • Cell Proliferation
  • Cochlea
  • Ear, Inner
  • Green Fluorescent Proteins
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nestin
  • Organogenesis
  • Reproducibility of Results

A septo-temporal molecular gradient of sfrp3 in the dentate gyrus differentially regulates quiescent adult hippocampal neural stem cell activation.

A converging body of evidence indicates that levels of adult hippocampal neurogenesis vary along the septo-temporal axis of the dentate gyrus, but the molecular mechanisms underlying this regional heterogeneity are not known. We previously identified a niche mechanism regulating proliferation and neuronal development in the adult mouse dentate gyrus resulting from the activity-regulated expression of secreted frizzled-related protein 3 (sfrp3) by mature neurons, which suppresses activation of radial glia-like neural stem cells (RGLs) through inhibition of Wingless/INT (WNT) protein signaling. Here, we show that activation rates within the quiescent RGL population decrease gradually along the septo-temporal axis in the adult mouse dentate gyrus, as defined by MCM2 expression in RGLs. Using in situ hybridization and quantitative real-time PCR, we identified an inverse septal-to-temporal increase in the expression of sfrp3 that emerges during postnatal development. Elimination of sfrp3 and its molecular gradient leads to increased RGL activation, preferentially in the temporal region of the adult dentate gyrus. Our study identifies a niche mechanism that contributes to the graded distribution of neurogenesis in the adult dentate gyrus and has important implications for understanding functional differences associated with adult hippocampal neurogenesis along the septo-temporal axis.

MeSH Terms

  • Aging
  • Animals
  • Animals, Newborn
  • Dentate Gyrus
  • Gene Expression Regulation, Developmental
  • Glycoproteins
  • Intracellular Signaling Peptides and Proteins
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neural Stem Cells
  • Neurogenesis
  • Neuroglia
  • RNA, Messenger
  • Time Factors