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    • oleuropein Inhibitor of DNA binding ID facilitates

    2018-10-20

    Inhibitor of DNA binding 1 (ID1) facilitates cell-cycle progression, inhibits differentiation in multiple cell types, and plays an essential role in the self-renewal of stem cells (Lasorella et al., 2014). It is sufficient for maintaining murine embryonic stem cell self-renewal and pluripotency in the absence of bone morphogenic protein (Ying et al., 2003), and maintains embryonic stem cell self-renewal by upregulation of Nanog and repression of Brachyury expression (Romero-Lanman et al., 2012). Loss of Id1 function leads to premature withdrawal of neuroblasts from the cell cycle and inappropriate expression of neural-specific markers, in addition to a defect in angiogenesis in the murine embryonic oleuropein (Lyden et al., 1999). High levels of Id1 expression define a subpopulation of GFAP+ cells in the subventricular zone (SVZ) of adult mouse brain that are bona fide B1-type adult neural stem cells (Nam and Benezra, 2009) and intermediate levels of Id1 are associated with the more committed progenitor C cells in the SVZ. In addition, this hierarchy is maintained during gliomagenesis (Barrett et al., 2012). Therefore, we hypothesized that ID1 might be a fate determinant of other adult stem cell populations. Here, we show that (1) ID1 expression in the gut is restricted to CBC cells and the +4 position, which corresponds to cells expressing LGR5 and BMI1, respectively, as well as TA cells; (2) these ID1+ cells are self-renewing, multipotent stem cells that are responsible for the long-term renewal of the gut epithelium in lineage-tracing experiments; (3) single Id1+ cells efficiently generate long-lived organoids resembling mature intestinal epithelium; and (4) knocking out Id1 in intestinal epithelial cells impairs LGR5+ stem cell function and sensitizes animals to chemical-induced injury to the colon.
    Results and Discussion
    Experimental Procedures
    Acknowledgments
    Introduction Macrocephaly, which is defined as having a head circumference greater than the 97th percentile on normal growth curves, can be caused by alterations in a number of genes, including the tumor-suppressor genes PTEN and TSC. Patients with these relatively rare mutations have a high risk of autism spectrum disorders (ASD) (Fidler et al., 2000; Klein et al., 2013; Zhou and Parada, 2012). The conditional deletion of PTEN in mice produces brain overgrowth due in part to a sustained increase in neural stem cell self-renewal and neurogenesis in the subventricular zone (SVZ) (Groszer et al., 2006; Gregorian et al., 2009). Both PTEN and TSC are negative regulators of the PI3K/AKT/mTOR signaling pathway, which is a central regulator of cellular growth and survival. In addition to overt macrocephaly, a more mild and pervasive brain overgrowth in ASD was recently identified in retrospective studies of head circumference (Courchesne et al., 2003; Schumann et al., 2010). Although direct evidence of a relationship between brain overgrowth and the onset of ASD pathology has yet to be demonstrated, induced brain overgrowth in some animal models has been shown to result in abnormal autism-associated behaviors (Fatemi et al., 2002; Bauman et al., 2013). In addition to strong evidence for the genetic transmission of autism, studies have shown that certain perinatal factors increase the risk for ASD and brain overgrowth (Nordahl et al., 2013; Bill and Geschwind, 2009). These environmental factors, through interactions with genetic susceptibility during critical periods of development, have the potential to play a significant role in the etiology of ASD (Voineagu et al., 2011; Hallmayer et al., 2011). One such environmental risk factor for ASD is the maternal inflammatory response (MIR) (Patterson, 2011). Clinical studies have identified a positive association between brain overgrowth and maternal inflammation, suggesting a pathogenic link between the immune system and brain growth in ASD (Sacco et al., 2007; Nordahl et al., 2013). Although the MIR has been linked to both autism and brain overgrowth, the mechanisms underlying its potential pathological effects remain undefined.