The production of gametes is pivotal to launching the next generation. To generate gametes, germline stem cells (GSCs) must exit the mitotic program, which governs self-renewal and transit amplification, and initiate the meiotic program. While several germ cell intrinsic mechanisms that repress the meiotic program during the mitotic phase have been described, little is known about how the mitotic program is regulated. We have identified a specialized transcriptional complex that permits the expression of a germline-specific ribosomal protein that regulates the mitotic program and the shift to meiosis. We discovered an unexpected role for the conserved Male-specific lethal 3 (Msl3) protein in regulating female germline mitotic phase transcription. In Drosophila, Msl3 is part of the Dosage Compensation Complex (DCC) that upregulates transcription from the X chromosome in males. We find that msl3 is expressed in the mitotic phase of the female germ line, where it acts independently of the DCC to both promote GSC maintenance and transition into meiotic fate. Our data suggest that Msl3 recruits the histone acetyltransferase (HAT) activity of the Ada2a-Containing (ATAC) complex. We found that loss of msl3 and ATAC complex components lead to reduced transcription of a ribosomal protein, RpS19b. We find that RpS19b is expressed specifically in the germline mitotic stages and propose that it controls translation of factors such as RNA binding protein Fox 1 (Rbfox1) to regulate the mitosis- to-meiosis switch. The objective of this proposal is to uncover how Msl3 regulates the transition from the mitotic- to-meiotic program via RpS19b. Our central hypothesis is that Msl3 recruits HAT activity via the ATAC complex to promote transcription of RpS19b, which in turn regulates Rbfox1 translation. We plan to test our hypothesis with the following three specific aims: 1) Determine how Msl3 promotes oogenesis. 2) Determine the role of HATs in Msl3-dependent transcription. 3) Uncover the role and mechanism of RpS19b in oogenesis. The rationale for the proposed work is that insight into Msl3-mediated regulation of the mitotic-to-meiotic transition will illuminate how functional oocytes are generated. In mammals, Msl3 is part of the Male Specific Lethal (MSL) complex, which regulates maintenance and differentiation from the pluripotency program, suggesting a potential conserved function of Msl3 in stem cell compartments.

Public Health Relevance

Germline stem cells (GSCs) self-renew and differentiate into gametes, but how this transition is regulated is not fully understood. Using Drosophila female GSCs as a model, we have determined that Male-specific lethal 3 (Msl3), a chromatin binding protein, as a regulator of self-renewal and differentiation. As Msl3 is conserved up to humans, we hope to use Drosophila as a model to better understand its contributions to fertility and birth defects.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Development - 2 Study Section (DEV2)
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Salazar, Desiree Lynn
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State University of New York at Albany
Schools of Arts and Sciences
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