There is no definitive evidence regarding how precursor cells in the neuroepithelium switch from generating neuroblasts to generating glioblasts. Studies on the generation of glia cell types, in particular astrocytes, have been hindered by the lack of markers for their precursors and by their extensive migratory pathways. The principal investigator speculates that the cell-type switched to glioblast is distinguished by the differential expression of specific adhesion and extracellular matrix (ECM) molecules, reflecting the differential expression of transcription factors. The developmentally controlled expression of the aggrecan gene in brain ventricular zones during the active period of neuronal migration and gliogenesis suggests an important role for this molecule in neuronal-glial interactions. However, the specific functions and interactions in which aggrecan is involved in vivo remain unclear and will require further investigation. On the basis of the investigator's preliminary results, two hypotheses can be put forth with respect to the function of aggrecan during this process: 1) changes in the composition and/or structure of the ECM may influence the switching of precursor cells differentiating from neuroblast to glioblast cell-fates, or may influence the final glial phenotype (oligodendrocyte or astrocyte) that the precursors can become, and 2) alternatively, aggrecan may regulate the level of cell proliferation or affect the migration of the precursor cells which populate the brain.

In order to distinguish between these possibilities a detailed study of aggrecan expression relative to that of different cell type markers, as well as of modifications in cell fate or proliferation associated with the lack of aggrecan expression in the aggrecan-deficient nanomelic mutant, will be the main focus of this proposal.

R03HD044677

2003-07-01

2006-06-30