Neural precursor cells (see Projects 1 and 2) will be transplanted into the brains of living animals to (1) assess their multipotentiality and differentiation capacity when they are exposed to the more complex cues of an in vivo environment, and (2) determine whether the cells are capable of becoming functionally active in the host nervous system. We will study as our model system the endogenous neural clock, located in the hypothalamic suprachiasmatic nucleus (SCN), that governs mammalian circadian rhythmicity; the features of this clock make it uniquely powerful system for analyzing the structure and function of cell transplants. Cultured neural precursor cells derived from the striata/ subventicular zone of the fetal ROSA26 mice expressing a Beta- galactosidase reporter transgene will be implanted into the region of the SCN of the brains of host animals whose circadian rhythmicity is absent or disordered. We will ask (A) What morphologies result from the differentiation of these cells in vivo, and do they include SCN-specific phenotypes? (B) Are transplanted cells integrated into the host brain at the implant site? (C) Can the transplants restore circadian function (locomotor rhythmicity) in deficient hosts? and (D) How does the local environment at the implant site influence transplant morphology, integration, and function? Hosts will include mice whose SCN is ablated by electrolytic lesion and embryonic intact and clock mutant mice or neonatal opossums who's SCN is undergoing neurogenesis. Our circadian transplant model provides a functionally-relevant, in vivo assay for studying the differentiation of precursor cell populations, their modulation by cytokines and environmental cues, and a first step towards realizing the possible therapeutic potential of these cells for central nervous system repair and as vehicles for gene delivery.
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