Regulation of adult stem cell function and identity by a histone variant and polycomb group proteins in the drosophila testis
- Jose Rafael Morillo Prado.
- Aug. 2012.
- Physical description
- online resource (xii, 119 pages) : illustrations (some color)
- Morillo Prado, Jose Rafael.
- Brown, Bryan Anthony thesis advisor (primary).
- Fuller, Margaret T., 1951- thesis advisor (primary).
- Lipsick, Joseph Steven, 1955- thesis advisor.
- Villeneuve, Anne, 1959- thesis advisor.
- Wysocka, Joanna, Ph. D. thesis advisor.
- Stanford University. Department of Developmental Biology.
- Stanford University. Committee on Graduate Studies. degree grantor.
- Includes bibliographical references (p. 112-119).
- Many adult tissues with short-lived cells such as blood and skin require a constant replacement of aging cells. This process is often accomplished by adult stem cells, both self-renew and give rise to differentiating progeny. The process of self-renewal and differentiation must be tightly controlled: failure to self-renew results in the loss of the stem cell population, and lack of differentiation impairs tissue function with dire consequences to the organism. The fate decisions of stem cells are guided by the interaction between extracellular signals from the local microenvironment and intrinsic factors that set the state of the cell, many of which are coordinated by transcriptional programs that are, in turn, is controlled by posttranslational modifications of histones or replacement of canonical histones with histone variants. Polycomb group (PcG) proteins partake in the modification of histones and influence the transcriptional state of genes. PcG proteins are involved in transcriptional regulation by inducing the methylation and ubiquitination of histone tails, which maintain the repression of target genes through cell divisions. Emerging evidence indicates that replacement of canonical histones with histone variants is also important in cell fate decisions. Here I show that PcG proteins Psc and Su(z)2 restrict proliferation and maintain the identity of the cyst stem cell (CySC) lineage in the Drosophila testis. Loss of Psc and Su(z)2 gene function in CySC but not in the germline stem cell (GSC) lineage resulted in the formation of a tumor composed of proliferative mutant cells of abnormal identity, likely due to the derepression of the Hox gene Abdominal-B. The resulting formation of tumor-like masses of proliferative cells interfered non-cell autonomously with maintenance of the germline most likely by displacing GSCs from their niche. I also show that the histone variant His2Av is required cell-autonomously for maintenance of adult stem cells in both somatic and germ cell lineages. GSCs lacking His2Av function were lost over time. Surprisingly, GSCs null mutant for His2Av gave rise to germ cells that underwent normal transit amplification divisions and differentiation to spermatocytes and spermatids. Similarly, CySCs lacking His2Av were also lost over time, but were able to give rise to differentiated cyst cells. My results indicate that His2Av and Stat92E likely maintain GSCs and CySCs independently. His2Av mutant GSCs expressed Stat92E and had properly oriented centrosomes, while Stat92E mutant GSCs expressed His2Av. My results expand knowledge chromatin states required for adult stem cell function, showing, for the first time, that a histone variant has a unique role in maintaining stem cells.
- Adult Stem Cells > metabolism
- Drosophila melanogaster > embryology
- Drosophila melanogaster > genetics
- Histones > genetics
- Polycomb Repressive Complex 1 > physiology
- Stem Cells > physiology
- Testis > metabolism
- Publication date
- Submitted to the Department of Developmental Biology and the Committee on Graduate Studies of Stanford University.
- Thesis (Ph.D.)--Stanford University, 2012.