Targeting prophet of PIT1 gene and designing mouse lines for cre -mediated gene targeting in somatotrophs.

Mouse models are invaluable for functional analysis of genes critical for pituitary development. Different alleles can be generated that vary in severity, allowing the dosage effect of genes to be ascertained, and alleles can be produced so that the genetic deficiency is induced at a particular time of development or in a specific tissue. Lesions in the prophet of PIT1 gene, PROP1, affect only the pituitary and are the most common cause of multiple pituitary hormone deficiencies in humans. To study the function of PROP1 in pituitary development, I generated a complete loss of function allele of Prop1 in mice using gene targeting. Homozygotes for the null allele exhibit respiratory distress and neonatal lethality that is secondary to pituitary hormone deficiency. These phenotypes are sensitive to genetic background. The animals that survive the perinatal period are dwarfs with hypogonadism, hypothyroidism, hypoglycemia, and alterations in the pituitary adrenal axis. An existing spontaneous allele has residual PROP1 function and is compatible with life but causes lack of GH, TSH, PRL and reduced gonadotropins. These studies help explain the variation in human patients with PROP1 deficiency and suggest that lesions in PROP1 may account for some cases of neonatal lethality with pituitary aplasia. Pitx2 is one of several genes that are critical for development of the pituitary and other organs required for viability. This makes it difficult to discover the role of these genes in specific mature pituitary cell types. To overcome this problem transgenic mouse lines were generated that express the site-specific DNA recombinase cre exclusively in the growth hormone producing cells of the pituitary gland. These lines are currently being used to evaluate the role of the homeobox gene Pitx2 in somatotrope development and function. They are an important resource for studying the role of other genes in growth hormone production.PhDAnimal PhysiologyBiological SciencesGeneticsMolecular biologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/123246/2/3068933.pd