The long term objective of this research program remains the analysis of the developmental consequences of overexpression of genes triplicated in the trisomy 16 (Ts16) mouse. Two such genes located on mouse chromosome 16 (MMU 16) encode preprosomatostatin (Smst) and a transcription factor, pit-1 (dwarf, dw). Although dwarf and Smst are not the same gene, dwarf mice express elevated levels of preprosomatostatin in various regions of their brains, and have premature loss of Smst expressing cells in regions of their hypothalami. The overall aims of this proposal are to determine whether the products of the Smst gene function to modulate growth and/or development and survival of neurons and glia in the early nervous system in normal, Ts16, and dwarf mice and thus to contribute to the structural and neurochemical deficits observed in Ts16 mice and dwarf mice. to dissect the neurobiological effects of excess somatostatin expression independent of the effects that arise from triplication of the dwarf locus in Ts16 mice, mice transgenic for the endogenous Smst gene will also be studied. Five separate lines of such Smst transgenic (SmstTg) mice have been developed, and differ in genetic background, levels of overexpression, and phenotype. Three of these SmstTg lines have been well characterized and exhibit both intrauterine and postnatal growth alterations and variable levels of overexpression of Smst in different regions of their brains. One line, SmstTg13, exhibits intrauterine and postnatal growth retardation, excess Smst expression, increased levels of proSRIF derived peptides, and cholinergic deficits, reminiscent of the phenotype of the dwarf mouse. The first specific aim is to characterize Smst expression in early brain development in normal, Ts16, Smst transgenic, and dwarf mice, and to correlate such expression with parameters of growth during the prenatal and postnatal period. The second specific aim is to examine the generation and survival of cholinergic neuron populations in the brain and spinal cord of these groups of mice relative to levels of Smst expression. The third specific aim is to analyze particular behavioral and neurochemical changes which occur in normal, SmstTg, and dwarf mice during the postnatal period, particularly changes which occur in spontaneous activity and in the parameters of the cholinergic system. Methods for RNA and DNA analysis and quantification, polymerase chain reaction and reverse transcription polymerase chain reaction, in situ hybridization, radioimmunoassay, immunocytochemistry, single pulse and cumulative cell birthdating, and light and electron microscopy will be used in these studies. Together, these studies will help us to obtain a greater understanding of the role of somatostatin in normal and abnormal development of the nervous system and the relationship between smst expression and the expression of the transcription factor, pit-1.
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