Molecular regulation of animal development
The Kimble lab investigates fundamental controls of animal development. Our work takes advantage of the genetic power and cellular simplicity of the nematode Caenorhabditis elegans, which can be viewed as the “E. coli of animal development”. Our findings rely on a variety of experimental strategies and have uncovered genes, proteins and pathways that control development in all animals, including humans.
Germline stem cells and their control
Germline stem cells are maintained by a combination of signaling from their external environment or “niche” and by intrinsic regulators that promote self-renewal or differentiation. In C. elegans, the single Distal Tip Cell (DTC) forms the niche for germline stem cells and uses Notch signaling to maintain germline stem cells. Our current work focuses on how germ cells respond to Notch signaling and what molecular regulators control the decision between stem cell maintenance and differentiation.
A regulatory network controls germline fates
The development of a cell as one particular cell type relies on key regulators that govern its fate. Importantly, those regulators themselves must be controlled so that cells develop in the right way and at the right time during development. Our work has outlined a molecular network that controls the decision between germline self-renewal and differentiation. Many of the regulators in the network control mRNA translation or stability, and as a result, we are particularly interested in RNA controls. We are also beginning to address how the network is modulated in response to physiological and environmental cues.
Regulation of the stem cell niche Asymmetric cell division is a major mechanism for generating cell diversity during animal development. Our work centers on the asymmetric cell division that generates that the Distal Tip Cell (which forms the niche for germline stem cells) and that also establishes polarity of the entire gonadal organ. This pivotal asymmetric cell division is sexually dimorphic, which provides an important entrée into understanding how asymmetric cell divisions can be regulated during development and evolution. We have discovered that the Wnt pathway activates the gene for the CEH-22/Nkx2.5 homeodomain transcription factor to specify the DTC niche fate.
The sperm/oocyte decision and its Chemical Reprogramming
Regulators of the sperm/oocyte decisionremain active to specify germ cells as sperm or oocyte during their continuous production in adults. We have used our knowledge of molecular controls of the sperm/oocyte decision to chemically reprogram adult germlines. The reprogramming of germ cell fates in C. elegans provides a powerful model for the analysis of molecular mechanisms of in vivo cell reprogramming and provides a paradigm that may facilitate pharmacological approaches to therapeutic cellular reprogramming in other organisms, including humans.