Molecular regulation of pluripotency in the mammalian germline (2016–2019)
Pluripotency of the male germline must be tightly balanced during embryonic development: sufficient numbers of pluripotent stem cells must be allocated for fertility, but unconstrained pluripotency gives rise to precursor cells for germ cell cancers (GCC). We recently discovered that the TGF¿¿ signalling molecule Nodal and its receptor Cripto function during the development of germ cells in male mouse embryos, apparently acting to maintain stem cell characteristics. Further, we have found ectopic expression of Nodal and Cripto in GCC. Therefore a thorough understanding of the regulation and downstream effects of Nodal/Cripto signalling in the germline, as we propose here, will be an essential basis for future investigations into male fertility and cancer. In this project we will apply our expertise and tools in developmental biology and molecular genetics to clarify the role of Nodal signalling during normal mouse germ cell development. Specifically we will: 1. Determine what regulates expression of Nodal/Cripto signalling components in germ cells 2. Examine knockout mouse models to define the in vivo role for Nodal and Cripto in male germ cell development 3. Study over-expression mouse models to determine whether downregulation of Nodal/Cripto signalling is required for germ cell differentiation Outcomes of this project will clarify the mechanism of a critical stop/go decision in fetal germ cell development, illuminate the molecular underpinnings of cell potency, and identify the signals that instruct stem cells to self-renew vs differentiate. Insights generated will be especially important in view of the rising tide of male infertility and GCC in the Australian population and worldwide.