The School of Molecular and Cellular Biology at the University of Illinois at Urbana-Champaign

The regenerative powers of many metazoans have intrigued biologists for generations and yet, the mechanisms involved in regenerative processes remain largely unknown. My laboratory uses the planarian flatworm, a classic subject of early regeneration experiments, to understand the molecular mechanisms underlying regeneration. The choice of planarians as a system to address the problem of regeneration is based upon: their remarkable developmental plasticity; the rapidity of their regenerative response; the ease with which they can be cultured in the laboratory; and the stem cell population that gives rise to their regenerative abilities.

After a planarian has been transected, the wounded area is rapidly covered by a thin layer of epidermal cells. Undifferentiated cells called neoblasts are then signaled to proliferate beneath the wound epithelium, giving rise to an unpigmented structure referred to as the regeneration blastema. As regeneration proceeds, neoblasts continue to accumulate within the blastema, causing it to grow exponentially. Within one week of the transection, differentiation of the missing structures occurs. In uninjured planaria, neoblasts are distributed throughout the parenchyma (mesenchyme) and, as the only mitotic cells in the animal, serve as the source of replacement cells during tissue renewal.

Research in my laboratory focuses on three main areas:

Control of the proliferation and differentiation of the regenerative stem cells: By combining studies of how the cell cycle is regulated in response to wounding, screens for stem cells markers, and functional studies using double-stranded RNA-mediated genetic interference (RNAi), we hope to understand the mechanisms by which stem cell proliferation is stimulated by wounding and how the differentiation of stem cells is choreographed to replace the missing structures.

The factors that regulate germ cell differentiation: Unlike most other metazoans, planarians do not segregate their germ cell lineage during embryogenesis. Instead, the gonads are formed in specific regions of the adult animal, when it attains the appropriate size. Thus, there must be cues that direct the neoblasts to form ovaries and testes at the appropriate time and in the appropriate place. The cues that guide this determination of the germ cells in planarians are completely unknown.

The species that we have been studying, Schmidtea mediterranea, provides a unique opportunity to study this issue. S. mediterranea exists in both sexually and asexually reproducing strains; the sexual organisms are hermaphroditic and produce egg capsules when mated with another planarian, whereas the asexual organisms reproduce strictly by fission. From a molecular genetic standpoint, the asexuals are interesting because they harbor a Robertsonian translocation that results in a switch from sexual to asexual reproduction. By screening for genes that are expressed in the sexual strain but lacking in the asexuals, we will identify markers for the germ cells, as well as genes involved in germ cell determination in this rather simple metazoan. Such studies should provide insights into the evolution of germ cell determination mechanisms.

Neural regeneration and plasticity: One of the truly fascinating aspects of planarian biology is the plasticity of the nervous system. In addition to the rapid regeneration of cephalic ganglia, ventral nerve cords, and all of the sensory structures, the nervous system is plastic enough to grow and shrink with the planarian, depending upon the availability of food. Due to a lack of appropriate markers, little is know about the process of nervous system regeneration in planarians, or to what extent cell turnover in the nervous system allows the plasticity seen during growth and degrowth. To identify nervous system markers, ESTs from head-specific cDNA libraries are being screened by sequence similarity and automated in situ hybridization. With such markers in hand, we can begin a detailed analysis of nervous system regeneration in the planarian. RNAi is being used to characterize the role of these neurally genes in neural regeneration.