Clipsham Robert, McCabe Edward R B
UCLA Molecular Biology Institute, Los Angeles, CA, USA.
Mol Genet Metab. 2003 Sep-Oct;80(1-2):81-120. doi: 10.1016/j.ymgme.2003.08.023.
DAX1 encoded by NR0B1, when mutated, is responsible for X-linked adrenal hypoplasia congenita (AHC). AHC is due to failure of the adrenal cortex to develop normally and is fatal if untreated. When duplicated, this gene is associated with an XY sex-reversed phenotype. DAX1 expression is present during development of the steroidogenic hypothalamic-pituitary-adrenal-gonadal (HPAG) axis and persists into adult life. Despite recognition of the crucial role for DAX1, its function remains largely undefined. The phenotypes of patients and animal models are complex and not always in agreement. Investigations using cell lines have proved difficult to interpret, possibly reflecting cell line choices and their limited characterization. We will review the efforts of our group and others to identify appropriate cell lines for optimizing ex vivo analysis of NR0B1 function throughout development. We will examine the role of DAX1 and its network partners in development of the hypothalamic-pituitary-adrenal/gonadal axis (HPAG) using a variety of different types of investigations, including those in model organisms. This network analysis will help us to understand normal and abnormal development of the HPAG. In addition, these studies permit identification of candidate genes for human inborn errors of HPAG development.
由NR0B1编码的DAX1发生突变时，会导致X连锁先天性肾上腺发育不全（AHC）。AHC是由于肾上腺皮质发育异常所致，若不治疗则会致命。该基因发生复制时，与XY性反转表型相关。DAX1在类固醇生成性下丘脑 - 垂体 - 肾上腺 - 性腺（HPAG）轴发育过程中表达，并持续至成年期。尽管认识到DAX1的关键作用，但其功能仍 largely undefined。患者和动物模型的表型复杂，且并不总是一致。使用细胞系进行的研究难以解释，这可能反映了细胞系的选择及其有限的特征。我们将回顾我们团队和其他团队为确定合适的细胞系以优化对NR0B1在整个发育过程中的功能进行离体分析所做的努力。我们将使用各种不同类型的研究，包括在模式生物中的研究，来研究DAX1及其网络伙伴在下丘脑 - 垂体 - 肾上腺/性腺轴（HPAG）发育中的作用。这种网络分析将帮助我们了解HPAG的正常和异常发育。此外，这些研究有助于识别HPAG发育先天性缺陷的人类候选基因。
