The gene regulatory mechanisms that program cell differentiation from proliferating precursor cells are fundamentally important for development, tissue homeostasis and cancer. Using the dramatic cellular differentiation program of spermatogenesis as a model stem cell lineage, we seek to understand the unique, cell-type specific transcription program initiated in the spermatocyte stage that sets cells up for terminal differentiation. Here we will investigate how cell-type specific transcriptional activators and repressors we have discovered in Drosophila, and the chromatin modifying complexes and transcription machinery they recruit, together specify the transcription program required for male gamete differentiation. We will investigate how both somatic specific and spermatid differentiation transcripts are kept silent in proliferating precursor cells and probe how testis-specific TAFs (homologs of components of the general Pol II transcription machinery), and a testis specific form of the normally repressive MuvB/dREAM complex work with the transcriptional co-activator Mediator to activate expression of meiotic cell cycle and spermatid differentiation genes. We will investigate how a testis-specific Rest-like Zn Finger protein expressed at the onset of spermatocyte differentiation acts in this context to block inappropriate spermatogonial and somatic differentiation programs in spermatocytes. Defects in either of these latter two gene regulatory mechanisms results in arrest of spermatogenesis at the G2/M transition of meiosis I and failure to initiate spermatid differentiation. Our work on the mechanism of action of cell-type specific transcription activating complexes and master transcriptional repressors in the Drosophila male germ line will provide paradigms for understanding how development programs terminal differentiation of specialized cell types. In addition, understanding the mode of action of the meiotic arrest gene circuitry of Drosophila may illuminate mechanisms underlying meiosis I maturation arrest infertility in man.

Public Health Relevance

In both embryonic and adult stem cell lineages, terminal differentiation genes repressed in precursor cells must be robustly activated in a cell type specific and gene-selective manner as cell differentiate, while transcripts specific to other tissues must be repressed to allow differentiation appropriate to the lineage. We will analyze both of these regulatory modes and how they collaborate to set up and execute the unique, cell- type specific spermatocyte gene expression program required for differentiation of male gametes. Our results will establish paradigms for how cell-type specific alternate forms of core gene regulatory complexes, coactivators, and lineage-specific repressors act to coordinate differentiation and illuminate mechanisms underlying meiosis I maturation arrest male infertility.

National Institute of Health (NIH)
Research Project (R01)
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Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
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Sledjeski, Darren D
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Stanford University
Anatomy/Cell Biology
Schools of Medicine
United States
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