There are two mouse dwarfing mutations that provide good models for studying the basis for induction of tissue specific transcription during embryogenesis. Both mutants lack the three pituitary cell types which produce prolactin, growth hormone, and thyroid stimulating hormone (TSH). The similarity of the mutant phenotypes suggests that the three missing cell types may derive from a common precursor cell and that at least two genes are involved in this differentiation pathway. Classical genetic and molecular biology will clarify how the affected genes normally interact and whether they have overlapping functions. Specifically, double heterozygotes and double mutants will be produced and the phenotypes characterized in terms of neurological, development, immune dysfunction and ablation of additional pituitary cell types. An intersubspecific backcross will be used to screen candidate genes for linkage to the Ames dwarf mutation (df) on chromosome 11 and for fine mapping of the df gene. Closely linked molecular probes will be used to generate a long range map of the df region using pulsed field gel electrophoresis. The df mutant was generated by X-irradiation, therefore the long range map may reveal evidence for a deletion or rearrangement, which would facilitate locating and subsequent cloning of the df gene. Linked molecular probes will be used to screen a yeast artificial chromosome (YAC) library of the mouse. Pituitary cDNA and cross species homology will be used to identify the df gene within the YACs. Identification of the mutant gene by reverse genetics will clarify the basis for the failure of progenitor cells to differentiate into hormone producing cells and expand our understanding of the basic cellular commitment process. %%% The anterior pituitary is composed of a number of cell types, each specialized in the synthesis and secretion of different hormones. This study will determine if the products of genes essential for the development of the specific cell types act independently in each cell or whether their expression affects the development of neighbor cells.
