Child Psychiatry Branch, National Institute of Mental Health, Bethesda, MD, USA.
Neuroimage. 2013 Dec;83:962-8. doi: 10.1016/j.neuroimage.2013.07.052. Epub 2013 Jul 25.
The capacity of sex to modify behavior in health and illness may stem from biological differences between males and females. One such difference--fundamental to the biological definition of sex--is inequality of X chromosome dosage. Studies of Turner Syndrome (TS) suggest that X-monosomy profoundly alters mammalian brain development. However, use of TS as a model for X chromosome haploinsufficiency is complicated by karyotypic mosaicism, background genetic heterogeneity and ovarian dysgenesis. Therefore, to better isolate X chromosome effects on brain development and identify how these overlap with normative sex differences, we used whole-brain structural imaging to study X-monosomic mice (free of mosaicism and ovarian dysgenesis) alongside their karyotypical normal male and female littermates. We demonstrate that murine X-monosomy (XO) causes (i) accentuation of XX vs XY differences in a set of sexually dimorphic structures including classical foci of sex-hormone action, such as the bed nucleus of the stria terminal and medial amygdala, (ii) parietal and striatal abnormalities that recapitulate those reported TS, and (iii) abnormal development of brain systems relevant for domains of altered cognition and emotion in both murine and human X-monosomy. Our findings suggest an unexpected role for X-linked genes in shaping sexually dimorphic brain development, and an evolutionarily conserved influence of X-linked genes on both cortical and subcortical development in mammals. Furthermore, our murine findings highlight the bed nucleus of the stria terminalis and periaqueductal gray matter as novel neuroanatomical candidates for closer study in TS. Integration of these data with existing genomic knowledge generates a set of novel, testable hypotheses regarding candidate mechanisms for each observed pattern of anatomical variation across XO, XX and XY groups.
性在健康和疾病中改变行为的能力可能源于男性和女性之间的生物学差异。其中一个差异——性别生物学定义的基础——是 X 染色体剂量的不平等。特纳综合征（TS）的研究表明，X 单体性深刻地改变了哺乳动物的大脑发育。然而，由于染色体镶嵌、背景遗传异质性和卵巢发育不良，TS 作为 X 染色体单倍不足的模型的使用变得复杂。因此，为了更好地分离 X 染色体对大脑发育的影响，并确定这些影响如何与正常性别差异重叠，我们使用全脑结构成像研究了 X 单体性（XO）小鼠（无镶嵌和卵巢发育不良）及其染色体正常的雄性和雌性同窝仔鼠。我们证明，鼠 X 单体性（XO）导致（i）在一组性二态性结构中，包括经典的性激素作用焦点，如终纹床核和内侧杏仁核，XX 与 XY 差异的加剧，（ii） recapitulates 报道的 TS 中那些的顶叶和纹状体异常，以及（iii）在鼠和人类 X 单体性中与改变的认知和情绪域相关的大脑系统的异常发育。我们的发现表明 X 连锁基因在塑造性二态性大脑发育中具有意想不到的作用，以及 X 连锁基因对哺乳动物皮质和皮质下发育的进化保守影响。此外，我们的鼠类研究结果强调了终纹床核和导水管周围灰质作为进一步研究 TS 的新的神经解剖候选物。将这些数据与现有的基因组知识整合，为观察到的 XO、XX 和 XY 组中每个解剖变异模式的候选机制生成了一组新的、可测试的假设。
