Constance L. Cepko
Professor and Associate Investigator
Howard Hughes Medical Institute
Harvard University Medical School
Harvard Medical School
200 Longwood Avenue
Boston, MA 02115
1986 Searle Scholar
Development of the Central Nervous SystemSeveral approaches to the study of CNS development are being used. One involves construction of a lineage map. The retina, cerebellum, cortex, and basal ganglia of rodents and chickens have been studied in this way. Currently, the chick forebrain and cerebellum are being mapped. Lineage analysis is being carried out in all of these areas using replication-incompetent retroviruses carying histochemical marker genes and genetic tags. To date, the results indicate that progenitors are multipotent with respect to cell type and, in some cases, with respect to the final location of daughter cells. Since lineage does not appear to play the only role in determination of cell fate, the environment must be critical. In order to focus on the role of the environment and the molecules that are most relevant for cell fate determination, we have chosen to focus on one area, the rodent retina. The overall immediate aim is to understand some of the molecular mechanisms that determine choice of cell type by retinal progenitor cells. Eventually, the mechanisms that underlie choice of transmitter type as well as synaptic partners will also be addressed.
In vitro cell cultures of retinal progenitor cells have been developed for use in several types of assays. The first goal was to determine if commitment events concerning cell type could occur in vitro. This was found to be true for several of the postnatally-generated cell types in rodent and an early-generated cell type in chick. The conditions that allow these events are now being dissected. It appears that photoreceptor development is influenced by taurine, EGF/TGFa, and CNFT/LIF. The role and mechanism of action of these factors is now being investigated. For early chick retinal cells, vertebrate notch controls the number of cells differentiating as ganglion cells. This was determined using antisense oligonucleotides directed against notch and a retrovirus vector transducing activated notch in vivo.
In a parallel approach, cDNA libraries have been constructed from the retina at different points in the developmental program. They are being screened by polymerase chain reaction and by using hybridization with a variety of probes from other systems. This is in order to determine if there is stage-specific expression of any molecules that have been implicated in otheer systems to play a role in development (e.g. tyrosine kinase genes, transcription factors, and homeobox genes). To date, a novel homeobox-containing gene from chick retina has been isolated and found to be expressed in a nasal-temporal gradient. Many novel and known receptor tyrosine kinases have also been identified.
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