DEVELOPMENT AND SURVIVAL OF THE ENDOCRINE HYPOTHALAMUS AND POSTERIOR PITUITARY GLD REQUIRES THE NEURONAL POU DOMAIN FACTOR BRN-2

Neurons comprising the endocrine hypothalamus are disposed in several nuclei that develop in tandem with their ultimate target the pituitary gland, and arise from a primordium in which three related class III P OU domain factors, Brn-2, Brn-4, and Brn-1, are initially coexpressed. Subsequently, these factors exhibit stratified patterns of ontogenic expression, correlating with the appearance of distinct neuropeptides that define three major endocrine hypothalamic cell types. Strikingly, deletion of the Brn-2 genomic locus results in loss of endocrine hypo thalamic nuclei and the posterior pituitary gland. Lack of Brn-2 does not affect initial hypothalamic developmental events, but instead resu lts in a failure of differentiation to mature neurosecretory neurons o f the paraventricular and supraoptic nuclei, characterized by an inabi lity to activate genes encoding regulatory neuropeptides or to make co rrect axonal projections, with subsequent loss of these neurons. Thus, both neuronal and endocrine components of the hypothalamic-pituitary axis are critically dependent on the action of specific POU domain fac tors at a penultimate step in the sequential events that underlie the appearance of mature cellular phenotypes.