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Robinton, Daisy

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Robinton, Daisy

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    Lin28a/b in the Regulation of Developmental Timing and Tumorigenesis
    (2016-05-10) Robinton, Daisy; Ruvkun, Gary; Daley, George Q.; Gregory, Richard; Gupta, Piyush; Pourquie, Olivier
    The heterochronic genes Lin28a/b and let-7 have long been known to play critical roles in the development of organisms from worms to humans. These highly conserved genes have emerged as factors that regulate self-renewal, proliferation, and differentiation in order to control tissue development, organismal growth, regeneration, and somatic reprogramming. The same principles that are regulated by LIN28 in development – the timing and balance of self-renewal and differentiation of stem cells and progenitors – are co-opted in tumors that have reactivated LIN28 to drive oncofetal programs. Many poorly differentiated, aggressive cancers overexpress LIN28, however, its role in tumor initiation or maintenance has not been definitively addressed. We demonstrate that LIN28B overexpression is sufficient to initiate hepatoblastoma and hepatocellular carcinoma in murine models. In aggressive MYC-driven tumors that exhibit Lin28b overexpression, genetic deletion or siRNA-mediated knockdown of Lin28b reduced tumor burden, extended latency, and prolonged survival. Therefore, multiple murine models demonstrate that Lin28b is both sufficient to induce liver cancer and necessary for tumor maintenance. To gain deeper insights into the functions of Lin28a/b, we turned to embryonic development for more clarity on the roles these paralogs play in their native context. We looked specifically to the impact of Lin28a/b on patterning of the mammalian posterior body, an area that has not previously been explored. In these studies, we used Lin28a and LIN28B gain-of-function models to demonstrate for the first time a dramatic increase in the number of vertebrae formed in mammals. Loss of endogenous Lin28a, but not Lin28b, induced a truncation in the vertebral axis reflected by a lesser number of caudal vertebrae. This result was phenocopied upon induction of the let-7g microRNA, a known repressor of Lin28a/b, whereas loss of let-7 family members modestly increased the number of caudal vertebrae. Like the Hox gene family, the complete molecular underpinnings of these phenotypes are not entirely clear, however let-7 dynamics and proliferation in the tail bud are partially responsible for the change in vertebrae number. These results underscore the essential functions Lin28a/b and let-7 have in developmental processes, and pave the way for a deeper understanding of critical aspects of mammalian development.