Stem cells have virtually unlimited proliferation capacity, allowing for self-renewal, as well as the ability for daughters to differentiate into specific cell types.  These two abilities are key to proper development and tissue homeostasis. A tight balance must be maintained between proliferation and differentiation in order for stem cells to function properly.  Over-proliferation can lead to tumour formation, while under-proliferation can lead to a loss of the stem cell population, subsequently resulting in the inability to form the desired tissue. Our research involves using the germ line of C. elegans as a model to study how the balance between proliferation and differentiation is achieved.  The major regulator of this balance in the C. elegans germ line is the highly evolutionarily conserved Notch signalling pathway.  Notch signalling also regulates the proliferation vs. differentiation decision in mammalian hematopoietic and neural stem cells.  Therefore, this may be a common means of regulating the balance between proliferation and differentiation.

C.elegans has two sexes, hermphrodite and male. The gonad in the hermaphrodite (top) has two arms that are virtually identical to one another. Each arm produces first sperm, then oocytes. The oocytes are fertilized as they move towards the uterus, which is common to both gonad arms. The male has only one gonad arm and produces only sperm. In both sexes, the proliferative (or stem) cells reside at the distal ends of the gonad arms (shown in green). As the cells move proximally towards the uterus, they enter into meiotic prophase (begin differentiation).

The conserved Notch signalling pathway controls the balance between proliferation and meiotic entry by promoting proliferation, but only in the most distal end of the gonad arm. We are studying other genes that function in regulating the balance between proliferation and differentiation. In particular, we are studying three teg genes (tumourous enhancer of glp-1(oz1120z120)). Mutations in these genes were isolated in mutant screen designed to identify mutations that enhance a weak glp-1 gain-of-function allele, resulting in a tumourous germ line. These genes are likely either negative regulators of Notch signalling, or function downstream of Notch signalling to promote meiotic entry. We have cloned one of these genes, teg-1, and found that it is expressed in the nuclei of all germ cells. We are currently mapping, cloning and characterizing three other genes and determining their epistatic relationships with other regulators of the proliferation vs. meiotic entry decision. We are also performing further genetic screens to identify other factors that are involved in regulating this decision.