Elucidating the role of TNFAIP2 in the dichotomous cell fate choice of germline and soma

• Applicant: Dr. Sarmistha Deb
• Subject Area: Developmental Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 464824884

Cells of the early embryo are able to make all the cell types of the adult body. This property is described as pluripotency. Just after the embryo implants in the womb, these pluripotent cells make the first and most important decision during development, whether they will generate germ (those cells that will eventually give rise to sperm or egg) or soma – the cells which will make up the rest of the adult body. How this fundamental choice is made in the embryo is not known. Hence, my objective is to further our understanding of this critical choice point and decipher how a cell makes the decision to enter either the germline or somatic lineages. My PhD work led to the identification of TNFAIP2 as a conserved regulator of pluripotency, in both planarians and mouse. Pluripotent cells that are deficient in TNFAIP2 lack the potential of generating soma, and I have preliminary evidence that suggests they instead have a bias towards germ cells. For instance, these cells activate the genes that are required and sufficient to drive germ cell development. Moreover, TNFAIP2 displays a mutually exclusive expression pattern with these germline genes, suggesting it acts as a regulator of germline entry. My future project will expand on this work and formally define the role of TNFAIP2 in mouse germline competence. I will test whether deletion of TNFAIP2 allows enhanced formation of germ cells and perform a reciprocal experiment to test if enforced expression drives somatic differentiation (at the expense of germ cells). I will then investigate if the role of TNFAIP2 is conserved in human. Indeed, I have preliminary data that indicates that expression of TNFAIP2 is associated with somatic differentiation of human pluripotent cells, consistent with my findings in mice. Furthermore, supporting this observation, re-analysis of published data reveals that expression of TNFAIP2 is downregulated in early human germ cells. I will build on these findings by directly assessing the role of TNFAIP2 in human germline differentiation, and subsequently work on the molecular mechanism by which it fulfills its function(s). Overall, my previous work and current preliminary data supports the tantalizing possibility that TNFAIP2 may fulfill a conserved and fundamental role in restricting entry to the germline, hence allowing appropriate somatic differentiation.

• DFG Programme: WBP Fellowship
• International Connection: United Kingdom
• Host: Dr. Harry Leitch