DEVELOPMENTAL DEFECTS OF THE VENTROMEDIAL HYPOTHALAMIC NUCLEUS AND PITUITARY GONADOTROPH IN THE FTZ-F1 DISRUPTED MICE

Ad4BP (or SF-1) has been identified as a transcription factor which re gulates all the steroidogenic P450 genes in the peripheral organs, and is encoded by the mammalian homologue of Drosophila FTZ-F1 gene, mRNA coding for Ad4BP was detected in the hypothalamus and pituitary of ra ts by RT-PCR. Immunohistochemical analyses using an antiserum to Ad4BP in the brain and pituitary revealed that the transcription factor is expressed in nuclei of the dorsomedial part of the ventromedial hypoth alamus (dm VMH) and in some subpopulation of the adenohypophysial cell s. Double immunostaining of the pituitary for Ad4BP and trophic peptid e hormones, FSH, TSH, and ACTH, indicated a restricted localization of Ad4BP to the gonadotroph, Disruption of the mouse Ftz-F1 gene was cla rified to induce severe defects in the organization of the dmVMH and t he function of the pituitary gonadotroph. However, some of the dm VMH neurons and pituitary gonadotrophs persisted, which provided a sharp c ontrast to complete agenesis of the peripheral steroidogenic tissues ( adrenal and gonads) in the mutant mouse. Additional abnormalities were seen in the ventrolateral part of VMH and dorsomedial hypothalamic nu cleus, both of which do not express Ad4BP but have strong reciprocal f iber-connections with the dm VMH. Aromatase P450-containing cells in t he medial preoptico-amygdaloid region, which were devoid of Ad4BP, per sisted even in the brain of the gene disrupted mice. The present resul ts clearly showed that the hypothalamic and pituitary Ad4BPs are essen tial to normal development of the functional VMH and gonadotroph throu gh some mechanism distinct from that in the peripheral steroidogenic t issues. (C) 1995 Wiley-Liss, Inc.