Fat-specific FUS-DDIT3-transgenic mice establish PPARgamma inactivation is required to liposarcoma development.
FUS-DDIT3 is a chimeric oncogene generated by the most common chromosomal translocation t(12;16)(q13;p11) associated to liposarcomas. The application of transgenic methods and the use of primary mesenchymal progenitor cells to the study of this sarcoma-associated FUS-DDIT3 gene fusion have provided insights into their in vivo functions and suggested mechanisms by which lineage selection may be achieved. These studies indicate that FUS-DDIT3 contributes to differentiation arrest acting at a point in the adipocyte differentiation process after induction of peroxisome proliferator-activated receptor gamma (PPARgamma) expression. To test this idea within a living mouse, we generated mice expressing FUS-DDIT3 within aP2-positive cells, because aP2 is a downstream target of PPARgamma expressed at the immature adipocyte stage. Here, we report that FUS-DDIT3 expression was successfully induced at the aP2 stage of differentiation both in vivo and in vitro. aP2-FUS-DDIT3 mice do not develop liposarcomas and exhibit an increase in white adipose tissue size. Consistent with in vivo data, mouse embryonic fibroblasts (MEFs) obtained from aP2-FUS-DDIT3 mice not only were capable of terminal differentiation but also showed an increased capacity for adipogenesis in vitro compared with wild-type MEFs. Taken together, this study provides genetic evidence that the presence of FUS-DDIT3 in an aP2-positive cell is not enough to cause liposarcoma development and establishes that PPARgamma inactivation is required for liposarcoma development.
Pérez-Mancera
Pedro Antonio
PA
Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas/Universidad de Salamanca, Campus Unamuno, 37007 Salamanca, Spain.
Vicente-Dueñas
Carolina
C
González-Herrero
Inés
I
Sánchez-Martín
Manuel
M
Flores-Corral
Teresa
T
Sánchez-García
Isidro
I
D017667:Adipocytes / Q000166:cytology*; D000818:Animals; D002454:Cell Differentiation; D002885:Chromosomes, Human, Pair 16; D002889:Chromosomes, Human, Pair 2; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D008080:Liposarcoma / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008819:Mice, Nude; D008822:Mice, Transgenic; D047495:PPAR gamma / Q000037:antagonists & inhibitors*; D011401:Promoter Regions, Genetic; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D034702:RNA-Binding Protein FUS / Q000235:genetics*; D051742:Transcription Factor CHOP / Q000235:genetics*; D014178:Translocation, Genetic
C497249:DDIT3 protein, human; D047495:PPAR gamma; D034702:RNA-Binding Protein FUS; D051742:Transcription Factor CHOP; D012313:RNA