Fetal Deficiency of Lin28 Programs Life-Long Aberrations in Growth and Glucose Metabolism

Shinoda, Gen; Shyh‐Chang, Ng; Soysa, T. Yvanka de; Zhu, Min; Seligson, Marc T.; Shah, Samar P.; Abo-Sido, Nora; Yabuuchi, Akiko; Hagan, John P.; Gregory, Richard I.; Asara, John M.; Cantley, Lewis C.; Moss, Eric G.; Daley, George Q.

doi:10.1002/stem.1423

Cited by 115 publications

(138 citation statements)

References 37 publications

(3 reference statements)

Supporting

Mentioning

128

Contrasting

Unclassified

Order By: Relevance

“…Moreover, Lin28 has been shown to promote glycolytic metabolism in tissues and cancer cells and thus is a central regulator of cellular bioenergetics ). It appears that Lin28 functions to balance the proliferative and metabolic needs of rapidly growing cells in the early embryo (Shinoda et al 2013b) and that this function becomes reactivated in many adult tumors. In cases of pediatric malignancy, Lin28 appears to prolong the embryonic patterns of tissue growth (as we showed here for Wilms tumor), which is likely the case for germ cell tumors and neuroblastoma.…”

Section: Discussionmentioning

confidence: 99%

Lin28 sustains early renal progenitors and induces Wilms tumor

et al. 2014

Self Cite

View full text Add to dashboard Cite

Wilms Tumor, the most common pediatric kidney cancer, evolves from the failure of terminal differentiation of the embryonic kidney. Here we show that overexpression of the heterochronic regulator Lin28 during kidney development in mice markedly expands nephrogenic progenitors by blocking their final wave of differentiation, ultimately resulting in a pathology highly reminiscent of Wilms tumor. Using lineage-specific promoters to target Lin28 to specific cell types, we observed Wilms tumor only when Lin28 is aberrantly expressed in multiple derivatives of the intermediate mesoderm, implicating the cell of origin as a multipotential renal progenitor. We show that withdrawal of Lin28 expression reverts tumorigenesis and markedly expands the numbers of glomerulus-like structures and that tumor formation is suppressed by enforced expression of Let-7 microRNA. Finally, we demonstrate overexpression of the LIN28B paralog in a significant percentage of human Wilms tumor. Our data thus implicate the Lin28/Let-7 pathway in kidney development and tumorigenesis. Wilms tumor, a pediatric kidney cancer affecting one in 10,000 children in North America, arises from the failure of embryonic nephrogenic cells to undergo terminal differentiation (Rivera and Haber 2005). The development of the kidney is a complex process that requires reciprocal inductive interactions between the ureteric bud (UB) and metanephric mesenchyme (MM), which leads to proliferation and expansion of the primitive cap mesenchyme (CM) (Grobstein 1955(Grobstein , 1956Hatini et al. 1996;Davidson 2009). The CM cells differentiate into mature nephrons by a mesenchymal-to-epithelial transition (MET). As they also possess self-renewal capacity, CM cells represent embryonic kidney stem cells (Kobayashi et al. 2008;Pleniceanu et al. 2010). CM cells proliferate and differentiate in the outer nephrogenic zone of the kidney until the second postnatal day in mice (Hartman et al. 2007) and the 36th week of gestation in humans (Hinchliffe et al. 1991), after which time all remaining CM cells synchronously differentiate to establish the final number of nephrons in the adult kidney (Hartman et al. 2007). Wilms tumor shares histological features with the developing kidney and is frequently associated with persistent areas of embryonic tissue known as nephrogenic rests, which contain blastemal cells with varying degrees of differentiation (Rivera and Haber 2005).Lin28 is an RNA-binding protein that regulates gene expression via two different mechanisms: one that blocks the processing of the Let-7 family of microRNAs (miRNAs) (Heo et al. 2008;Newman et al. 2008;Rybak et al. 2008;Viswanathan et al. 2008)

show abstract

Section: Discussionmentioning

confidence: 99%

Lin28 sustains early renal progenitors and induces Wilms tumor

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…Initial investigations have revealed roles for LIN28 in glucose uptake and tolerance, diabetes, sickle cell anemia and cancer (de Vasconcellos et al, 2014;Perez et al, 2013;Shinoda et al, 2013;Shyh-Chang et al, 2013;Zhu et al, 2011), suggesting that the modulation of LIN28 activity might be an attractive therapeutic approach. For example, the expression of LIN28 in cultured, sickle-shaped erythrocytes resulted in a significant decrease in their sickle morphology compared with control erythrocytes (de Vasconcellos et al, 2014).…”

Section: Lin28 In Disease and Therapymentioning

confidence: 99%

LIN28: roles and regulation in development and beyond

2015

View full text Add to dashboard Cite

LIN28 is an RNA-binding protein that is best known for its roles in promoting pluripotency via regulation of the microRNA let-7. However, recent studies have uncovered new roles for LIN28 and have revealed how it functions, suggesting that it is more than just a regulator of miRNA biogenesis. Together, these findings imply a new paradigm for LIN28 -as a gatekeeper molecule that regulates the transition between pluripotency and committed cell lineages, in both let-7-dependent and let-7-independent manners. Here, we provide an overview of LIN28 function in development and disease.

show abstract

“…S1E) prompted us to examine whether they play redundant roles in brain development. It has been reported that Lin28b null mice exhibit no detectable developmental phenotypes (Shinoda et al, 2013). We crossed Lin28a +/− with Lin28b +/− mice to produce compound heterozygotes, which were intercrossed to generate various genotypes including double-homozygous knockout (DKO) offspring.…”

Section: Lin28a and Lin28b Are Both Required For Normal Npc Proliferamentioning

confidence: 99%

“…Lin28b knockout mice were kindly provided by the Dr George Daley laboratory, and have been described elsewhere (Shinoda et al, 2013).…”

Section: Lin28a/b Mutant and Lin28a Transgenic Micementioning

confidence: 99%

Lin28 promotes the proliferative capacity of neural progenitor cells in brain development

et al. 2015

Self Cite

View full text Add to dashboard Cite

Neural progenitor cells (NPCs) have distinct proliferation capacities at different stages of brain development. Lin28 is an RNA-binding protein with two homologs in mice: Lin28a and Lin28b. Here we show that Lin28a/b are enriched in early NPCs and their expression declines during neural differentiation. Lin28a single-knockout mice show reduced NPC proliferation, enhanced cell cycle exit and a smaller brain, whereas mice lacking both Lin28a alleles and one Lin28b allele display similar but more severe phenotypes. Ectopic expression of Lin28a in mice results in increased NPC proliferation, NPC numbers and brain size. Mechanistically, Lin28a physically and functionally interacts with Imp1 (Igf2bp1) and regulates Igf2-mTOR signaling. The function of Lin28a/b in NPCs could be attributed, at least in part, to the regulation of their mRNA targets that encode Igf1r and Hmga2. Thus, Lin28a and Lin28b have overlapping functions in temporally regulating NPC proliferation during early brain development.

show abstract

Fetal Deficiency of Lin28 Programs Life-Long Aberrations in Growth and Glucose Metabolism

Cited by 115 publications

References 37 publications

Lin28 sustains early renal progenitors and induces Wilms tumor

Lin28 sustains early renal progenitors and induces Wilms tumor

LIN28: roles and regulation in development and beyond

Lin28 promotes the proliferative capacity of neural progenitor cells in brain development

Contact Info

Product

Resources

About