2014) only if the overexpression was driven using a Wt1 cre line. An earlier study showed that overexpression of RNA-binding protein lin28 results in Wilms tumor ( Urbach et al.
Wilms tumors ariseįrom the uninduced metanephric mesenchyme, where the Wilms tumor 1 ( WT1) gene is expressed. However, there was no overgrowth or evidence of kidney abnormalities or Wilms tumor. Of the features of Perlman syndrome, including bradykinesia, abnormal curvature of the spine, and highly penetrant genitourinary Embryonic day 18.5 embryos exhibited some In the case of both alleles, homozygous mutant animals were perinatal lethal. Further analysis showed that this latter mutation results in a destabilized protein and is functionally With the help of a CRISPR/Cas9 approach, a Dis3l2-null mouse strain was generated by deleting the catalytic domain as well as a strain that models a common exon deletion found Of the microRNA let7 family members observed. In neither case was any change in the expression
Overgrowth free download 2016 series#
Using genome editing, series of DIS3L2-null human cell lines as well as knockout mouse embryonic stem cells were created. Human cell lines and mouse model systems. 2014).Īccordingly, the investigators tested the hypothesis that DIS3L2 loss of function leads to alteration in let7 levels in both In a mouse model through inhibition of the oncogenic target lin28, which is overexpressed in Wilms tumor ( Viswanathan et al. Moreover, microRNA let7 is known to function as a Wilms tumor suppressor 2015), characterized by dysregulated microRNA levels. Recent genetic evidence has shown microRNA processing gene (MIRPG) mutations associated with Wilms tumor ( Rakheja et al.
In this context, DIS3L2 has been shown to be the only known exoribonuclease for degrading preprocessed forms of microRNA DIS3L2 functions as a 3′–5′ exoribonuclease that preferentially degrades oligouridylated RNAs ( Lubas et al. (2018) addressed the mechanisms underlying Perlman syndrome, which is an autosomal recessive syndrome arising through mutation ofĭIS3L2 on chromosome 2q37 ( Astuti et al. (2018) in the previous issue of Genes & Development, highlight the significance of IGF2 up-regulation in the context of Perlman syndrome and Wilms tumor, respectively. That increased IGF2 expression is an important contributing factor in both BWS and Wilms tumor ( Caspary et al. Work with animal models has provided evidence Furthermore, increased expression of IGF2 through these mechanisms is commonly found as a somatic event in Wilms tumors. The imprinted IGF2 gene through either paternal 11p15 disomy or loss of imprinting of the maternal allele. It is well established that BWS arises through increased expression of Tumors, including hepatoblastoma and neuroblastoma. However, individuals with BWS and SGBS may also develop other To tumors, particularly the pediatric kidney cancer Wilms tumor. Patients with these overgrowth syndromes also have a predisposition Resulting in altered expression of key developmental genes. These arise through genetic alterations, including chromosomal translocations, loss of imprinting, duplication, or mutations
Well as heart defects (for review, see Kamien et al. Overgrowth syndromes, including Beckwith-Wiedemann syndrome (BWS), Simpson-Golabi-Behmel syndrome (SGBS), and Perlman syndrome,Īre characterized by macrosomia, facial dysmorphism, intellectual disabilities, and, in some cases, renal abnormalities as Thus, augmented IGF2 expression seems to be a common downstream factor in both tissue overgrowth and Wilms tumor through several alternative mechanisms. Levels of transcription factor pleomorphic adenoma gene 1 (PLAG1) that in turn activates IGF2 expression. 996–1007) show that microRNA processing gene mutations in Wilms tumor lead to an increase in the In a second study in this issue of Genes & Development, Chen and colleagues (pp. By analyzing nephron progenitor cells derived from their newly createdĭis3l2 mutant mouse lines, the investigators showed that DIS3L2 loss of function leads to up-regulation of IGF2 independently of the let7 microRNA pathway. 903–908) investigated the molecular mechanisms by which mutations in the gene encoding the RNAĭegradation component DIS3L2 lead to Perlman syndrome. In the previous issue of Genes & Development, Hunter and colleagues (pp. Tumor, increased levels of IGF2 have been shown to be causally related to the disease manifestation. In the case of the Beckwith-Wiedemann overgrowth syndrome and in Wilms Overgrowth syndromes such as Perlman syndrome and associated pediatric cancers, including Wilms tumor, arise through geneticĪnd, in certain instances, also epigenetic changes.
0 kommentar(er)
