(from the applicant s abstract) The long term goal of this project is to elucidate the cellular and molecular mechanisms that regulate pattern of neural connections during visual system development. In the developing mammalian central nervous system, there is a massive over production and subsequent partial elimination of neurons and the selective stabilization/elimination of immature axon segments. The investigator proposes an examination of the effects on retinal ganglion cell (RGC) survival and connectivity of two complimentary manipulations: 1) Chronic delivery of excess neurotrophins to selected retinal targets in developing hamsters will be achieved by implantation of cell lines genetically engineered to overexpress neurotrophins. The hamster retinal projection system is a well-established model for studying the over production and subsequent partial elimination of immature neurons and their connections and the underlying competitive interactions among developing neurons and their axons. 2) Chronic neurotrophin deprivation in the developing retinal projection system of mice will be produced by null mutations of one or more neurotrophin genes. Two important aspects of these experiments are noted: they emphasize the rarely studied role of neurotrophins in determining the survival of immature axon trunks and branches; and, they investigate the combined actions of multiple neurotrophins and temporal changes in the relative dependence of developing neurons on different neurotrophins. The experiments will examine the role of competition for neurotrophins during development in the control of programmed retinal ganglion cell death in the selective stabilization/elimination of immature retinal ganglion cell axon segments. Programmed cell death and changes in neurotrophin expression occur in several human diseases and after axotomy. Changes in the pattern of neural connections and in neurotrophin expression occur within the visual system as a consequence of abnormal visual experience due to various peripheral visual defects early in life. Thus, understanding the role of neurotrophins in programmed cell death and the development of neuronal connectivity may suggest strategies to ameliorate the deficits associated with these conditions and with various developmental disorders.
