Our lab studies the earliest stages of embryogenesis to understand how single-celled eggs develop into complex multicellular embryos. We focus on the choice between soma and germline, one of the first developmental decisions faced by embryos. Our goal is to identify and characterize the molecular mechanisms that activate embryonic development, polarize embryos, and distinguish between somatic and germline cells, using Caenorhabditis elegans as a model system.
Oocyte-to-Embryo Transition: Driven by Meiosis
The beginning of development is marked by a remarkable transition: the quiescent oocyte is transformed into a dynamic embryo ready to differentiate into many cell types. We identified minibrain kinase 2 (MBK-2), a member of the evolutionarily conserved dual-specificity, tyrosine-regulated (DYRK) family of kinases, as a candidate master regulator of the oocyte-to-embryo transition. MBK-2 phosphorylates oocyte proteins shortly after fertilization to trigger their degradation, or change their activity, in preparation for embryogenesis. Surprisingly, MBK-2 is not activated by fertilization but by progression through the meiotic divisions. Premature entry into meiotic M phase in unfertilized oocytes is sufficient to activate MBK-2 and initiate aspects of embryonic development. We have identified two cell cycle regulators that contribute to MBK-2 activation. CDK-1 directly phosphorylates MBK-2 to stimulate its activity, and the anaphase-promoting complex (APC) stimulates the degradation of proteins that sequesters MBK-2 at the cell periphery. Our findings indicate that, in addition to its well-known role in regulating chromosome dynamics, the meiotic cell cycle triggers egg-wide developmental changes essential for the initiation of embryonic development.
In this research we seek to understand how zygotes become polarized along the anterior/posterior axis and how they use this information to segregate cell fate determinants to different ends of the growing embryo. We have identified one symmetry-breaking mechanism involving a direct interaction between the sperm-donated centrosome and the polarity regulator PAR-2. Localization of PAR-2 to the membrane nearest the sperm centrosome triggers the sorting of other PAR proteins into distinct membrane domains. We also have identified a direct interaction between the kinase PAR-1 and the determinant MEX-5, which polarizes the distribution of MEX-5 in the cytoplasm. These studies have begun to identify the biochemical interactions that lead to spatial patterning of the zygote.
Specification of Germ Cell Fate
Among the factors that are asymmetrically segregated in the zygote are the P granules. P granules are clusters of RNA and RNA-binding proteins that segregate asymmetrically with the nascent germline. P granule asymmetry is a classic example of cytoplasmic partitioning of germline determinants, thought to specify germ cell fate. We identified a mutant (pptr-1) where P granule proteins and RNAs are partitioned equally to all cells. Surprisingly, pptr-1 mutants still form a germline and are fertile, except at high temperatures. These findings suggest that embryonic P granules do not specify germ cell fate but may protect the nascent germline from stress.
This work is also supported by the National Institutes of Health.
As of May 30, 2012