Laboratory Research Interests

Mouse mutants provide a mechanism for identifying genes important in organogenesis and serve as animal models of human disease. We have focused on the genes responsible for several mouse mutations that map to the central region of mouse Chromosome 11. We have generated an extensive comparative map that facilitates correlation of mouse and human mutations.
     The Ames dwarf is a recessive mutation in a homeobox transcription factor, Prop1. Defective mice have pituitary cytodifferentiation failure and reduced cell proliferation early in organogenesis. Molecular genetic analyses have demonstrated that Prop1 is required for the transcriptional silencing and activation of the homeobox genes Rpx and Pit.1 Comparative genetic mapping predicts that the counterpart to Ames dwarf maps to human Chromosome 5.
     The vestigial tail mutation is characterized by abnormal development of the neural tube and vertebrae. We have shown that the defect results from reduced expression of Wnt3a, a secreted protein that exhibits homology to the Drosophila wingless gene. More severe loss of Wnt3a function results in caudal region defects including spina bifida. This suggests the potential contribution of the human Wnt3a gene to human birth defects.
     The spasmodic and oscillator mice are defects in the alpha 1 subunit of the glycine inhibitory neurotransmitter receptor. Spasmodic mice have a point mutation in the receptor which causes partial loss of function and produces in a mild startle defect. The oscillator mice have a deletion that causes a complete loss of function, resulting in progressive neurological symptoms and juvenile death. The demonstration that patients with startle defects have point mutations in the human gene, underlines the utility of mouse mutants as models for human disease.
     We are carrying out phenotypic characterization and genetic mapping of the recessive deafness mutation, shaker-2. Our comparative map suggests that this mouse mutation corresponds to the human hereditary deafness locus, DFNB3.
     In addition to the analysis of spontaneous mouse mutants, we emphasize a variety of approaches to understanding pituitary development. Ablation of gonadotrope and thyrotrope cell lineages with specifically targeted diphtheria toxin transgenes has demonstrated the ability of other pituitary cell types to develop in their absence. A homeobox transcription factor, Ptx2, is found in both gonadotrope and thyrotrope cells, suggesting a potential role for Ptx2 in cell fate determination. Gene targeted mice with pituitary defects resulting in hypogonadism and hypothyroidism have revealed distinct proliferative responses of thyrotropes and gonadotropes to thyroid hormone. Thus, both genetically engineered mice and spontaneous mutants have contributed to our understanding of pituitary organogenesis.