SF1--KEY MEDIATOR OF ENDOCRINE DEVELOPMENT AND FUNCTION

孤儿核受体类固醇生成因子1 （SF-1）最初是作为细胞色素P450类固醇羟化酶的调节因子被分离出来的，在内分泌发育和功能中起着重要作用。SF-1基因敲除小鼠缺乏肾上腺和性腺，垂体促性腺功能受损，缺乏下丘脑腹内侧核（VMH），这是一个与食欲控制和生殖行为相关的下丘脑区域。正在进行的研究试图扩大我们对SF-1的多效性作用的理解，并分离基因敲除表型的主要成分和次要成分。正在开发的组织特异性敲除技术将用于在单个位点特异性地破坏编码SF-1的基因，包括：VMH、垂体促性腺激素、支持细胞或颗粒细胞。另外，肾上腺移植将恢复SF-1基因敲除小鼠的肾上腺皮质功能，允许在肾上腺皮质类固醇水平正常的情况下对VMH消融小鼠进行分析。相关的一系列实验将使用绿色荧光蛋白（GFP）或β -半乳糖苷酶（LacZ）转基因，在SF-1调控序列的指导下，在下丘脑切片制备中体外跟踪表达SF-1的神经元，比较野生型和SF-1敲除小鼠的VMH发育情况。最后，我们将使用区域特异性消融术来研究将肾上腺划分为制造矿性皮质激素的外肾小球带和制造糖皮质激素的内束状/网状带的机制。这些研究将为SF-1在内分泌发育和功能中发挥多重作用的途径提供新的见解。

The orphan nuclear receptor steroidogenic factor1 (SF-1), originally isolated as a regulator of the cytochrome P450 steroid hydroxylases, plays essential roles in endocrine development and function. SF-1 knockout mice lack adrenal glands and gonads, have impaired pituitary gonadotrope function, and lack the ventromedial hypothalamic nucleus (VMH), a hypothalamic region linked to appetite control and reproductive behavior. Ongoing studies seek to expand our understanding of these pleiotropic roles of SF-1 and to separate primary versus secondary components of the knockout phenotype. The developing technology for tissue- specific knockouts will be used to disrupt the gene encoding SF-1 specifically within individual sites, including: the VMH, pituitary gonadotropes, Sertoli cells, or granulosa cells. Alternatively, adrenal transplants will restore adrenocortical function in SF-1 knockout mice, permitting analyses of VMH- ablated mice in the setting of normal levels of adrenocortical steroids. A related series of experiments will use green fluorescent protein (GFP) or beta-galactosidase (LacZ) transgenes directed by SF-1 regulatory sequences to follow SF-1 expressing neurons ex vivo in hypothalamic slice preparations, comparing VMH development in wild-type and SF-1 knockout mice. Finally, we will use zone-specific ablation to investigate the mechanisms that compartmentalize the adrenal gland into the outer zona glomerulosa, which makes mineralocorticoids, and the inner zonae fasciculata/reticularis, which make glucocorticoids. These studies will provide novel insights into the ways in which SF-1 exerts its multiple actions in endocrine development and function.