Developmental defects of the ventromedial hypothalamic nucleus and pituitary gonadotroph in the Ftz‐F1 disrupted mice

Abstract

Ad4BP (or SF-1) has been identified as a transcription factor which regulates 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 rats 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 hypothalamus (dmVMH) and in some subpopulation of the adenohypophysial cells. Double immunostaining of the pituitary for Ad4BP and trophic peptide hormones, FSH, TSH, and ACTH, indicated a restricted localization of Ad4BP to the gonadotroph. Disruption of the mouse Ftz-FI gene was clarified to induce severe defects in the organization of the dmVMH and the function of the pituitary gonadotroph. However, some of the dm VMH neurons and pituitary gonadotrophs persisted, which provided a sharp contrast 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 nucleus, both of which do not express Ad4BP but have strong reciprocal fiber-connections with the dmVMH. Aromatase P450-containing cells in the medial preoptico-amygdaloid region, which were devoid of Ad4BP, persisted even in the brain of the gene disrupted mice. The present results clearly showed that the hypothalamic and pituitary Ad4BPs are essential to normal development of the functional VMH and gonadotroph through some mechanism distinct from that in the peripheral steroidogenic tissues. 8 1995 Wiley-Liss, Inc.

Requirement of the orphan nuclear receptor SF-1 in terminal differentiation of ventromedial hypothalamic neurons

“…VMN neurons send projections to adjacent hypothalamic regions and to other brain regions, including the bed nucleus of stria terminalis and the amygdala of limbic system (Altman and Bayer, 1986;Luiten et al, 1987;Swanson, 1987;Canteras et al, 1994). Although the precise molecular and chemical nature of the VMN circuitry remains to be defined, recent studies have proposed that the orphan nuclear receptor steroidogenic factor 1 (SF-1) is required for proper VMN development and function (Ikeda et al, 1995;Shinoda et al, 1995;Majdic et al, 2002).…”

“…It is well established that SF-1 is an essential regulator in endocrine tissue and organ development. Indeed, targeted disruption of sf-1 in mice results in gonadal and adrenal agenesis, as well as the complete loss of pituitary gonadotropes (Ingraham et al, 1994;Luo et al, 1994;Sadovsky et al, 1995;Shinoda et al, 1995). SF-1 also regulates multiple targets that mediate normal adult endocrine physiology (reviewed in Parker, 1998;Hammer and Ingraham, 1999) and controls male sexual differentiation by regulating three important male hormones, including the Müllerian inhibiting substance, steroidogenic enzymes for testosterone synthesis and Insl-3, which is required for testicular descent (for review, see Roberts et al, 1999).…”

“…SF-1 also regulates multiple targets that mediate normal adult endocrine physiology (reviewed in Parker, 1998;Hammer and Ingraham, 1999) and controls male sexual differentiation by regulating three important male hormones, including the Müllerian inhibiting substance, steroidogenic enzymes for testosterone synthesis and Insl-3, which is required for testicular descent (for review, see Roberts et al, 1999). Consistent with SF-1's role in male development, sf-1 null (−/−) mice have female external genitalia regardless of their sex chromosomal complement Sadovsky et al, 1995;Shinoda et al, 1995). More recently, phenotypic sex reversal of XY genotypes in humans has been associated with a partial loss of SF-1 function (Achermann et al, 1999(Achermann et al, , 2002.…”

“…Previous analyses of sf-1 −/− mice report an apparent change in the cytoarchitecture of the VMN as assessed by the absence of a prominent condensed nucleus, an indistinct cell-free neuropil zone, and an increased number of neuroblasts in the paraventricular zone (Ikeda et al, 1995;Shinoda et al, 1995). Impaired VMN development in sf-1 −/− mice was explained as either a failure of VMN aggregation and organization or the regression of VMN neurons at late stages of development, analogous to the prominent cell death accounting for adrenal and gonadal agenesis in sf-1 −/− mice (Ikeda et al, 1995;Shinoda et al, 1995).…”

“…Previous analyses of sf-1 −/− mice report an apparent change in the cytoarchitecture of the VMN as assessed by the absence of a prominent condensed nucleus, an indistinct cell-free neuropil zone, and an increased number of neuroblasts in the paraventricular zone (Ikeda et al, 1995;Shinoda et al, 1995). Impaired VMN development in sf-1 −/− mice was explained as either a failure of VMN aggregation and organization or the regression of VMN neurons at late stages of development, analogous to the prominent cell death accounting for adrenal and gonadal agenesis in sf-1 −/− mice (Ikeda et al, 1995;Shinoda et al, 1995). More recently, detailed histological analyses reported an expansion of glutamic acid decarboxylase (GAD) 67 and estrogen receptor (ER)α-positive neurons in the presumptive embryonic sf-1 −/− VMN, leading to the suggestion that VMN precursors either fail to aggregate, survive, or differentiate properly (Dellovade et al, 2000).…”