Noncanonical Transmission Of Biological Information And Master-Regulation Of Signaling By The Zinc Finger Proteins MSTR-1 And MSTR-2
Student: Matthew Eroglu
Supervisor: Dr. Brent Derry
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Abstract
Heritable information is encoded in nucleic acids and transmitted by an immortal germ lineage. Failure of germ cells to clear DNA damage or maintain small RNA expression leads to progressive sterility (germline mortality) over multiple generations due to accumulation of defects such as telomere erosion or transposon mobilization. Here, I show that solid-phase protein amyloids, which I propose to term ‘fluorosomes’ for their intrinsic fluorescence, are inherited transgenerationally and transmit the epigenetic information required for proper germ cell sex determination and germline immortality. I identify two genes, which I term multigenerational sterility and temperature regulated (F22D6.2/mstr-1 and F56F3.4/mstr-2), that when ablated lead to transgenerational accumulation of these fluorosomes and progressive transformation of germ cells from spermatogenic to oogenic fates. Among its key targets, MSTR-1 restricts expression of the sex determinant GLD-1 from spermatogenic cells, whereas in mstr mutants GLD-1 protein but not mRNA accumulates ectopically over several generations, transforming sperm-fated germ cells to oocytes. I further chronicle the discovery of these genes and the work that led to them, from investigation of their roles in cell signaling to the serendipitous discovery of their roles in germline function. Briefly, I show that insulin-like growth factor receptor DAF-2 signaling regulates DAF-16/FOXO dependent and independent networks to modulate LET-60/Ras function in the soma. The FOXO independent mechanism relies on the transcription factor PQM- 1, which is regulated by the SGK-1 kinase. The transcriptional target of PQM-1, mstr-1, regulates diverse cell signalling pathways important for multiple developmental processes, including vulval cell fate specification, germline proliferation, and longevity. Overall, my work reveals a post-transcriptional transgenerational epigenetic mechanism of trait transmission and demonstrates that germline immortality can be lost independently of DNA or RNA maintenance.