Sunday, May 18, 2025
5/18/2025
RUNX proteins define opposing fates in the male germline - PROJECT SUMMARY / ABSTRACT Compelling evidence from human epidemiological studies and model systems indicate that many adult diseases can be traced to deficits far earlier in development. As many cell lineages are supported by resident stem cells throughout adulthood, disruptions in the stem cell formation can have lasting impacts that manifest as a number of diseases or cancer. Our goal is to use the male germline as a model to better understand the process by which developmental precursors form tissue-specific stem cells that will ultimately support cell lineages long into adulthood. The critical factors that promote establishment of germline stem cells, that lead to adult infertility if disrupted, remain unknown. Thus, the field lacks a clear picture of the developmental regulators that coordinate stem cell formation. Modern technological advances such single-cell ‘omics approaches have begun annotating the complexities of germline stem cell formation to determine the essential players, but the functional networks are not clear. Here, we have integrated single-cell ‘omics approaches and identified the RUNX family as a set of transcription factors that are integral for prepubertal development in the male germline. Our recently published work determined that disruption of the RUNX family leads to failures in both self-renewing and differentiation functions with the male germline during prepubertal development. How the RUNX family accomplishes this balance of two opposing fates remains unknown, but our preliminary studies suggest that each function is coordinated by different members of the RUNX family. Thus, in Specific Aim 1, we will functionally evaluate the roles of RUNX1 and RUNX3 in balancing germ cell fate towards either proliferation and self-renewal or differentiation. In Specific Aim 2, we will evaluate how the RUNX family accomplishes this balance despite having largely overlapping consensus binding motifs for DNA and a common co-factor in CBFb. Finally, Specific Aim 3 will explore the fate of RUNX1- and RUNX3-labeled germ cells through lineage tracing approaches. Collectively, elucidating the mechanisms that establish and balance fate in the germline has the potential to translate into diagnostic, prevention, or treatment avenues for infertility with developmental origins. Furthermore, RUNX proteins are not unique to the germline and instead, span other stem cell-based lineages as well. Thus, we anticipate that our findings will contribute fundamental knowledge for a greater understanding of how tissue- specific stem cells balance fate and function across multiple lineages.
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