The pituitary gland is a neuroendocrine organ that produces and releases peptide hormones from specialized cells in the anterior lobe. Pituitary development is controlled by the combined activity of extrinsic signaling molecules and intrinsic transcription factors. Pitx2 encodes a homeobox transcription factor that is expressed in embryonic and adult pituitary gland. Individuals heterozygous for a mutant allele of PITX2 have Rieger syndrome (RGS), a disorder that is characterized by defects in eyes, teeth and umbilicus, and occasionally heart and pituitary. Most PITX2 lesions cause loss of function suggesting that Pitx2 gene dosage is critical for normal development. This hypothesis was tested by manipulating the activity of Pitx2 genes in mice. The targeted inactivation of Pitx2 in mice revealed its essential role in development of the eyes, heart, lungs, pituitary and ventral body wall. Pitx2 is required for the expansion of Rathke's pouch and survival of the precursors of terminally differentiated hormone producing cells. The size of the pituitary gland decreases as Pitx2 expression is reduced across an allelic series. Increased apoptosis is responsible for the extreme hypopituitarism of Pitx2 -/- mice. In addition, fewer pituitary cell types undergo specification in animals with reduced Pitx2 dosage. Mechanistically this is due to the failure of several lineage transcription factors, including Gata2, Sf1, Egr1 and Pit1 , to be expressed at normal levels. Elevated levels of Pitx2 also interfere with normal pituitary gland development in transgenic mice. More luteinizing hormone producing gonadotropes are formed in response to increased Pitx2 activity, revealing a direct correlation between Pitx2 gene dosage and gonadotrope specification. Thus, pituitary gland development is dependent upon a precise level of Pitx2. These studies provided a mechanistic understanding of Pitx2 gene dosage effects on pituitary development and explain the basis for RGS phenotype in patients with gain and loss of function mutations in PITX2. The model I developed for proliferation and cell death may be applicable to understanding the hypopituitarism characteristic of several other pituitary transcription factor mutants.Ph.D.Biological SciencesNeurosciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/132939/2/3058053.pd
