Neural Development Unit, UCL Institute of Child Health, London, UK.
Dev Biol. 2010 Jan 15;337(2):351-62. doi: 10.1016/j.ydbio.2009.11.005. Epub 2009 Nov 10.
Foregut division-the separation of dorsal (oesophageal) from ventral (tracheal) foregut components-is a crucial event in gastro-respiratory development, and frequently disturbed in clinical birth defects. Here, we examined three outstanding questions of foregut morphogenesis. The origin of the trachea is suggested to result either from respiratory outgrowth or progressive septation of the foregut tube. We found normal foregut lengthening despite failure of tracheo-oesophageal separation in Adriamycin-treated embryos, whereas active septation was observed only in normal foregut morphogenesis, indicating a primary role for septation. Dorso-ventral patterning of Nkx2.1 (ventral) and Sox2 (dorsal) expression is proposed to be critical for tracheo-oesophageal separation. However, normal dorso-ventral patterning of Nkx2.1 and Sox2 expression occurred in Adriamycin-treated embryos with defective foregut separation. In contrast, Shh expression shifts dynamically, ventral-to-dorsal, solely during normal morphogenesis, particularly implicating Shh in foregut morphogenesis. Dying cells localise to the fusing foregut epithelial ridges, with disturbance of this apoptotic pattern in Adriamycin, Shh and Nkx2.1 models. Strikingly, however, genetic suppression of apoptosis in the Apaf1 mutant did not prevent foregut separation, indicating that apoptosis is not required for tracheo-oesophageal morphogenesis. Epithelial remodelling during septation may cause loss of cell-cell or cell-matrix interactions, resulting in apoptosis (anoikis) as a secondary consequence.
前肠分隔-将背侧（食管）与腹侧（气管）前肠成分分开-是胃呼吸发育中的一个关键事件，并且在临床出生缺陷中经常受到干扰。在这里，我们研究了前肠形态发生的三个突出问题。气管的起源被认为要么来自呼吸生长，要么来自前肠管的渐进性分隔。我们发现阿霉素处理的胚胎中尽管气管食管分离失败，但前肠仍正常延长，而只有在正常前肠形态发生中才观察到活跃的分隔，表明分隔起主要作用。Nkx2.1（腹侧）和 Sox2（背侧）表达的背腹模式被认为对气管食管分离至关重要。然而，在有缺陷的前肠分离的阿霉素处理的胚胎中，Nkx2.1 和 Sox2 表达的正常背腹模式发生。相比之下，Shh 表达动态地从腹侧向背侧转移，仅在正常形态发生过程中发生，特别是表明 Shh 参与了前肠形态发生。死亡细胞定位于融合的前肠上皮嵴，阿霉素、Shh 和 Nkx2.1 模型中这种凋亡模式受到干扰。然而，令人惊讶的是，凋亡抑制基因 Apaf1 突变体中的细胞凋亡遗传抑制并没有阻止前肠分离，这表明细胞凋亡对于气管食管形态发生不是必需的。分隔过程中的上皮重塑可能导致细胞-细胞或细胞-基质相互作用的丧失，从而导致凋亡（失巢凋亡）作为次要后果。
