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My laboratory uses the Drosophila male germ line as a model to investigate how self-renewal, proliferation and differentiation are regulated in adult stem cell lineages. The central characteristic of adult stem cells is their long-term capacity to divide as relatively undifferentiated precursors while also producing daughter cells that initiate differentiation. Understanding the mechanisms that regulate stem cell specification and the choice between stem cell self-renewal and differentiation is crucial for realizing the potential of stem cells for regenerative medicine. We are using the Drosophila male germ line as a powerful genetic system to identify both the cell autonomous determinants and the extrinsic cell-cell interactions that govern stem cell specification, self-renewal, and differentiation. One of the great advantages of this system is that stem cells can be studied in situ, in the context of their normal support cells. Our results indicate that signals from surrounding somatic support cells specify asymmetric division of male germ line stem cells by inducing one daughter cell to self-renew stem cell identity while directing the other daughter cell to differentiate. A second focus of our work concerns how the developmental program directs cellular differentiation. Fundamental cellular functions like the cell cycle, the cytoskeleton, and the general transcription machinery are remodeled during development to give rise to specialized cell types. Several lines of research in our laboratory have recently converged on the molecular mechanisms underlying the developmentally programmed switch from proliferation to differentiation, a key regulatory point in the adult stem cell lineages that underlie tissue maintenance and repair. Failure to cleanly execute this switch may contribute to genesis of cancer. Our results implicate a number of molecular and cellular mechanisms in regulating this critical switch. We find that RNA binding proteins involved in translational control and alternative splicing act cell autonomously to regulate the cessation of proliferation and that progression of differentiation requires communication from associated somatic support cells. We discovered that a developmentally regulated alternate choice of site at which certain nascent transcripts are cut to form 3’ ends, leading to production of novel mRNA isoforms with shortened 3’UTRs, controls dramatic changes in the suite of proteins expressed in differentiating spermatocytes compared to proliferating spermatogonia. We found that dramatic changes in chromatin open over 2000 new promoters with novel core sequence structure to turn on the new cell type specific transcription program when cells initiate spermatocyte differentiation. Some of the earliest genes turned on in this differentiation program encode chromatin associated proteins that prevent spurious opening of normally cryptic promoters, thus preventing massive misexpression of genes associated with the wrong cell type. Other transcripts upregulated with differentiation onset encode cell type-specific translational regulators that delay production of core G2/M cell cycle machinery to program the extended G2 phase of meiotic prophase. Our goal over the next 5 years is to map how these processes collaborate to form the regulatory circuitry that initiates then executes the switch from proliferation to differentiation.
Testing the Safety and Tolerability of CX-4945 in Patients With Recurrent Medulloblastoma Who May or May Not Have Surgery
This is a multi center, Phase I, Phase II and surgical study of the CX-4945 drug
(silmitasertib sodium) for patients with recurrent SHH (Sonic Hedgehog) medulloblastoma
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