<i>Lin28a</i> Regulates Germ Cell Pool Size and Fertility

Shinoda, Gen; Soysa, T. Yvanka de; Seligson, Marc T.; Yabuuchi, Akiko; Fujiwara, Yuko; Huang, Pei Yi; Hagan, John P.; Gregory, Richard I.; Moss, Eric G.; Daley, George Q.

doi:10.1002/stem.1343

Cited by 47 publications

(50 citation statements)

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“…Previously, we and others have shown that LIN28 plays an important role in germ cell development (West et al 2009;Shinoda et al 2013a) and is associated with human germ cell tumors (Gillis et al 2011;Murray et al 2013). Thus, we endeavored to overexpress Lin28 in PGCs by crossing mice containing a Lox-stop-Lox-Lin28a cassette (LSL-Lin28a) (Supplemental Fig.…”

Section: Lin28 Overexpression During Embryonic Kidney Development Leamentioning

confidence: 94%

Lin28 sustains early renal progenitors and induces Wilms tumor

et al. 2014

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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)

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Section: Lin28 Overexpression During Embryonic Kidney Development Leamentioning

confidence: 94%

Lin28 sustains early renal progenitors and induces Wilms tumor

et al. 2014

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“…This was confirmed by examining inducible let-7 transgenic mice, which overexpress let-7 miRNA (Shinoda et al 2013). Thus, expression of lin28 in the early ovary is critical for the down-regulation of miRNA let-7, which allows for the proliferation of PGCs necessary for normal adult ovarian function (Shinoda et al 2013). To determine if lin28 was equally important in growing oocytes and/or early embryonic development, a transgenic RNAi mouse was generated in which lin28a and lin28b were selectively knockeddown in growing oocytes (Flemr et al 2014).…”

Section: Mirna In Ovarian Developmentmentioning

confidence: 81%

“…Because let-7 miRNA are downstream targets of lin28, it was theorized that overexpression of let-7 would mimic loss of lin28. This was confirmed by examining inducible let-7 transgenic mice, which overexpress let-7 miRNA (Shinoda et al 2013). Thus, expression of lin28 in the early ovary is critical for the down-regulation of miRNA let-7, which allows for the proliferation of PGCs necessary for normal adult ovarian function (Shinoda et al 2013).…”

Section: Mirna In Ovarian Developmentmentioning

confidence: 87%

“…lin28 is an RNA-binding protein that down-regulates the biogenesis of let-7, a large family of tumor suppressor miRNAs. Recent studies have reported the involvement of this pathway in the control of PGC proliferation in both males and females, as lin28 knockout mice produce fewer germ cells than control mice (West et al 2009;Shinoda et al 2013). In the adult male, spermatogonial stem cells compensate for this early reduction.…”

Section: Mirna In Ovarian Developmentmentioning

confidence: 99%

“…In the adult male, spermatogonial stem cells compensate for this early reduction. However, because female germ cells do not proliferate in the adult, female lin28 knockout mice suffer a significant reduction in fertility owing to loss of PGCs, resulting in a reduction in the size of the germ cell pool of the adult female (Shinoda et al 2013). Because let-7 miRNA are downstream targets of lin28, it was theorized that overexpression of let-7 would mimic loss of lin28.…”

Section: Mirna In Ovarian Developmentmentioning

confidence: 99%

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LIN28A Marks the Spermatogonial Progenitor Population and Regulates Its Cyclic Expansion

et al. 2014

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One of the hallmarks of highly proliferative adult tissues is the presence of a stem cell population that produces progenitor cells bound for differentiation. Progenitor cells undergo multiple transit amplifying (TA) divisions before initiating terminal differentiation. In the adult male germline, daughter cells arising from the spermatogonial stem cells (SSCs) undergo multiple rounds of TA divisions to produce undifferentiated clones of interconnected 2, 4, 8 and 16 cells, collectively termed Aundifferentiated (Aundiff) spermatogonia, before entering a stereotypic differentiation cascade. Although the number of TA divisions markedly affects the tissue output both at steady state and during regeneration, mechanisms regulating the expansion of the TA cell population are poorly understood in mammals. Here, we show that mice with a conditional deletion of Lin28a in the adult male germline, display impaired clonal expansion of the progenitor transit amplifying Aundiff spermatogonia. The in vivo proliferative activity of Aundiff spermatogonial cells as indicated by BrdU incorporation during S phase was reduced in the absence of LIN28A. Thus contrary to the role of LIN28A as a key determinant of cell fate signals in multiple stem cell lineages, in the adult male germline it functions as an intrinsic regulator of proliferation in the population of Aundiff TA spermatogonia. In addition, neither precocious differentiation nor diminished capacity for self-renewal potential as assessed by transplantation was observed, suggesting that neither LIN28A itself, nor the pool of Aal progenitor cells, substantially contribute to the functional stem cell compartment.

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Lin28a Regulates Germ Cell Pool Size and Fertility

Cited by 47 publications

References 20 publications

Lin28 sustains early renal progenitors and induces Wilms tumor

Lin28 sustains early renal progenitors and induces Wilms tumor

MicroRNA in Ovarian Biology and Disease

LIN28A Marks the Spermatogonial Progenitor Population and Regulates Its Cyclic Expansion

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