Schilham M W, Oosterwegel M A, Moerer P, Ya J, de Boer P A, van de Wetering M, Verbeek S, Lamers W H, Kruisbeek A M, Cumano A, Clevers H
Department of Immunology, University Hospital, Utrecht, The Netherlands.
Nature. 1996 Apr 25;380(6576):711-4. doi: 10.1038/380711a0.
A striking example of the relationship between regulation of transcription and phenotype is the central role of the Y-chromosomal gene Sry in mammalian sex determination. Sry is the founding member of a large family of so-called Sox genes. During murine embryogenesis, the transcriptional activator Sox-4 is expressed at several sites, but in adult mice expression is restricted to immature B and T lymphocytes. Using targeted gene distruption, we have found that SOX-4(-/-) embryos succumb to circulatory failure at day E14. This was a result of impaired development of the endocardial ridges (a specific site of Sox-4 expression) into the semilunar valves and the outlet portion of the muscular ventricular septum. The observed range of septation defects is known as 'common arterial trunk' in man. We studied haemopoiesis in lethally irradiated mice reconstituted with SOX-4(-/-) fetal liver cells and found that a specific block occurred in B-cell development at the pro-B cell stage. In line with this, the frequency and proliferative capacity of IL-7-responsive B cell progenitors in fetal liver were severely decreased in vitro.
转录调控与表型之间关系的一个显著例子是Y染色体基因Sry在哺乳动物性别决定中的核心作用。Sry是一个所谓Sox基因大家族的创始成员。在小鼠胚胎发育过程中，转录激活因子Sox - 4在多个部位表达，但在成年小鼠中，其表达仅限于未成熟的B和T淋巴细胞。通过基因靶向破坏，我们发现SOX - 4(-/-)胚胎在E14天时死于循环衰竭。这是由于心内膜嵴（Sox - 4表达的一个特定部位）发育成半月瓣和肌肉性室间隔出口部分受损所致。观察到的分隔缺陷范围在人类中被称为“共同动脉干”。我们研究了用SOX - 4(-/-)胎肝细胞重建的经致死性照射小鼠的造血过程，发现B细胞发育在原B细胞阶段出现了特异性阻滞。与此一致的是，胎肝中IL - 7反应性B细胞祖细胞的频率和增殖能力在体外严重降低。
