HYPOTHALAMIC RECONSTRUCTION USING NEURAL PRECURSOR CELLS

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DESCRIPTION: (Verbatim from the Applicant's Abstract) The discovery of self-renewing, multipotent neural precursor cells has raised hopes for their possible therapeutic utility, either for neural repair through cell replacement or as gene-delivery vehicles. Transplantation is a key strategy for testing the differentiation capacity and functional activity of such cells; when precursor cells obtained from one brain region are transplanted to another region, they appear to differentiate into neuronal and glial phenotypes appropriate to the implantation site. Whether the cells actually integrate in a regionally-specific, physiologically-relevant fashion remains unanswered. In this application, we will address this question by capitalizing on the unique anatomy, physiology, behavior, and molecular genetics of two hypothalamic neuronal systems that have not been previously exploited as engraftment targets for transplanted precursor cells. The suprachiasmatic nucleus (SCN) is the site of an endogenous clock that regulates circadian locomotor rhythmicity, a behavior that is abolished in mice homozygous for a mutation of the clock gene. The magnocellular division of the paraventricular nucleus (PVN) is the site of arginine vasopressin (AVP)-secreting neurons that regulate water balance, a function that is lost in mice with diabetes insipidus bearing a null mutation of the AVP gene. We will transplant a prototypic neural precursor cell line (C17.2; as well as C17.2NT-3, a modified clone overexpressing neurotrophin-3) into the telencephalic vesicle of embryonic mice and then examine the mice postnatally to address three questions: (A) Do engrafted precursor cells assume the morphologies, peptidergic phenotypes, and efferent projections characteristic of neurons indigenous to the SCN and PVN? (B) Can engrafted precursor cells respond to natural stimuli in ways that emulated the response of neurons indigenous to the SCN and PVN? (C) Will engrafted precursor cells in the SCN and PVN restore defective behaviors in homozygous clock and AVP-deficient mutant mice exhibiting circadian arrhythmicity and diabetes insipidus, respectively? The answers to these questions are initial steps towards establishing the circadian and hypothalamo-neurohypophyseal systems as potentially powerful models for analyzing the structural and functional plasticity of implanted precursor cells.