Balzer E, Heine C, Jiang Q, Lee VM, Moss EG.. LIN28 alters cell fate succession and acts independently of the let-7 microRNA during neurogliogenesis in vitro. Development 137: 891-900
Department of Molecular Biology, The University of Medicine and Dentistry of New Jersey, Stratford, NJ 08084, USA.Development (Impact Factor: 6.46). 03/2010; 137(6):891-900. DOI: 10.1242/dev.042895
LIN28 is an RNA-binding protein that is expressed in many developing tissues. It can block let-7 (Mirlet7) microRNA processing and help promote pluripotency. We have observed LIN28 expression in the developing mouse neural tube, colocalizing with SOX2, suggesting a role in neural development. To better understand its normal developmental function, we investigated LIN28 activity during neurogliogenesis in vitro, where the succession of neuronal to glial cell fates occurs as it does in vivo. LIN28 expression was high in undifferentiated cells, and was downregulated rapidly upon differentiation. Constitutive LIN28 expression caused a complete block of gliogenesis and an increase in neurogenesis. LIN28 expression was compatible with neuronal differentiation and did not increase proliferation. LIN28 caused significant changes in gene expression prior to any effect on let-7, notably on Igf2. Furthermore, a mutant LIN28 that permitted let-7 accumulation was still able to completely block gliogenesis. Thus, at least two biological activities of LIN28 are genetically separable and might involve distinct mechanisms. LIN28 can differentially promote and inhibit specific fates and does not function exclusively by blocking let-7 family microRNAs. Importantly, the role of LIN28 in cell fate succession in vertebrate cells is analogous to its activity as a developmental timing regulator in C. elegans.
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- "On a cellular level, Lin28a and Lin28b operate in separate compartments of the cell (Piskounova et al. 2011). Lin28a and Lin28b exert most of their effects through inhibition of let-7 levels but also have let-7 independent functions (Polesskaya et al. 2007, Balzer et al. 2010, Qiu et al. 2010, Peng et al. 2011, Wilbert et al. 2012). For example, it has been shown that Lin28a can bind mRNA directly and stimulate translation (Polesskaya et al. 2007, Qiu et al. 2010) via motifs that are found in many genes (Peng et al. 2011, Wilbert et al. 2012). "
ABSTRACT: Growth and pubertal timing differ in boys and girls. Variants in/near LIN28B associate with age at menarche (AAM) in genome-wide association studies and some AAM-related variants associate with growth in a sex-specific manner. Sex-specific growth patterns in response to Lin28b perturbation have been detected in mice, and overexpression of Lin28a has been shown to alter pubertal timing in female mice. To investigate further how Lin28a and Lin28b affect growth and puberty in both males and females, we evaluated Lin28b loss-of-function (LOF) mice and Lin28a gain-of-function (GOF) mice. Because both Lin28a and Lin28b can act via the conserved microRNA let-7, we also examined let-7 GOF mice. As reported previously, Lin28b LOF led to lighter body weights only in male mice while Lin28a GOF yielded heavier mice of both sexes. Let-7 GOF mice weighed less than controls, and males were more affected than females. Timing of puberty was assessed by vaginal opening (VO) and preputial separation (PS). Male Lin28b LOF and male let-7 GOF, but not female, mice displayed alteration of pubertal timing, with later PS than controls. In contrast, both male and female Lin28a GOF mice displayed late onset of puberty. Together, these data point toward a complex system of regulation by Lin28a, Lin28b, and let-7, in which Lin28b and let-7 can impact both puberty and growth in a sex-specific manner, raising the possibility that this pathway may contribute to differential regulation of male and female growth and puberty in humans.
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- "Furthermore, miRNAs stimulate RNA-silencing complexes to induce degradation, destabilization, and/or translational inhibition of target mRNAs (Bartel, 2009; Guo et al., 2010; Huntzinger and Izaurralde, 2011) and are seemingly involved in almost all cellular events, including the determination of cell fate (Ebert and Sharp, 2012; Friedman et al., 2009). In the developing mammalian CNS, various miRNAs participate in the control of neural stem cell self-renewal, proliferation, and differentiation (Balzer et al., 2010; Cimadamore et al., 2013; Li and Jin, 2010; Naka-Kaneda et al., 2014; Neo et al., 2014; Qureshi and Mehler, 2012; Shibata et al., 2011; Visvanathan et al., 2007; Yoo et al., 2009; Zhao et al., 2009). This study identifies miR-153 as a regulator of the initiation of gliogenesis in the developing CNS. "
ABSTRACT: Mammalian neural stem/progenitor cells (NSPCs) sequentially generate neurons and glia during CNS development. Here we identified miRNA-153 (miR-153) as a modulator of the temporal regulation of NSPC differentiation. Overexpression (OE) of miR-153 delayed the onset of astrogliogenesis and maintained NSPCs in an undifferentiated state in vitro and in the developing cortex. The transcription factors nuclear factor I (NFI) A and B, essential regulators of the initiation of gliogenesis, were found to be targets of miR-153. Inhibition of miR-153 in early neurogenic NSPCs induced precocious gliogenesis, whereas NFIA/B overexpression rescued the anti-gliogenic phenotypes induced by miR-153 OE. Our results indicate that miR-mediated fine control of NFIA/B expression is important in the molecular networks that regulate the acquisition of gliogenic competence by NSPCs in the developing CNS. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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- "This is important in the regulation of differentiation (15,16), especially as LIN28 and let-7 form a regulatory negative feedback loop (17). Interestingly, let-7-independent translation regulation by LIN28 occurs before the let-7-dependent step in Caenorhabditis elegans (18,19). LIN28 enhances translation, in a let-7-independent manner, of mRNAs important for cell growth in embryonic stem cells via the recruitment of RNA helicase A to polysomes (20–22). "
ABSTRACT: LIN28 function is fundamental to the activity and behavior of human embryonic stem cells (hESCs) and induced pluripotent stem cells. Its main roles in these cell types are the regulation of translational efficiency and let-7 miRNA maturation. However, LIN28-associated mRNA cargo shifting and resultant regulation of translational efficiency upon the initiation of differentiation remain unknown. An RNA-immunoprecipitation and microarray analysis protocol, eRIP, that has high specificity and sensitivity was developed to test endogenous LIN28-associated mRNA cargo shifting. A combined eRIP and polysome analysis of early stage differentiation of hESCs with two distinct differentiation cues revealed close similarities between the dynamics of LIN28 association and translational modulation of genes involved in the Wnt signaling, cell cycle, RNA metabolism and proteasomal pathways. Our data demonstrate that change in translational efficiency is a major contributor to early stages of differentiation of hESCs, in which LIN28 plays a central role. This implies that eRIP analysis of LIN28-associated RNA cargoes may be used for rapid functional quality control of pluripotent stem cells under manufacture for therapeutic applications.
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