Crisera C A, Maldonado T S, Kadison A S, Li M, Longaker M T, Gittes G K
Laboratory of Developmental Biology and Repair, New York University Medical Center, New York, New York, 10016, USA.
J Surg Res. 2000 Aug;92(2):245-9. doi: 10.1006/jsre.2000.5850.
We have recently proposed that the "distal esophagus" in esophageal atresia with tracheo-esophageal fistula (EA/TEF) is actually embryologically derived from the middle branch of a trifurcation of the embryonic lung bud, which subsequently grows caudally in the foregut to connect with the developing stomach. We hypothesized that differential mRNA expression of the lung-specific patterning transcription factor, thyroid transcription factor 1 (TTF-1), in the developing fistula tract in TEF relative to the bronchi (the other branches of the lung bud trifurcation) might explain the unique nonbranching pattern of growth of the fistula tract.
EA/TEF was induced in Sprague-Dawley rat embryos via intraperitoneal injection of 2.2 mg/kg adriamycin into pregnant dams on Days 6-9 of gestation. The foregut from embryos developing EA/TEF and from control embryos (no adriamycin) were isolated on Gestational Days 13.5, 15.5, and 17.5 (term = 21 days). Some were processed for whole-mount in situ hybridization for TTF-1, while others were embedded and sectioned for histologic analysis via in situ hybridization for TTF-1.
The expression of the respiratory-specific transcription factor TTF-1 is conserved in the epithelium of the developing fistula tract in TEF. The pattern of expression of TTF-1 in the fistula tract mirrors the expression in the large airways of the developing lungs, despite the fact that the fistula tract does not form secondary branches to give rise to a lung.
The fistula tract in TEF is a respiratory-derived structure that expresses the lung-specific transcription factor TTF-1 throughout its development in the foregut. Contrary to the patterning role that it normally plays in the developing lung, TTF-1 does not induce branching morphogenesis in the fistula tract. Thus, the nonbranching pattern of growth of the fistula tract may be attributable to local mesenchymal-epithelial interactions that override TTF-1 patterning activity.
我们最近提出，食管闭锁合并气管食管瘘（EA/TEF）中的“食管远端”实际上在胚胎学上起源于胚胎肺芽三叉分支的中间分支，该分支随后在前肠中向尾端生长并与发育中的胃相连。我们假设，相对于支气管（肺芽三叉分支的其他分支），气管食管瘘发育中的瘘管中肺特异性模式转录因子甲状腺转录因子1（TTF-1）的mRNA表达差异，可能解释瘘管独特的非分支生长模式。
在妊娠第6至9天，通过向妊娠的Sprague-Dawley大鼠母鼠腹腔注射2.2 mg/kg阿霉素，诱导胚胎发生EA/TEF。在妊娠第13.5、15.5和17.5天（足月为21天），分离发育EA/TEF的胚胎和对照胚胎（未注射阿霉素）的前肠。一些用于TTF-1的全组织原位杂交，另一些进行包埋和切片，通过TTF-1原位杂交进行组织学分析。
呼吸特异性转录因子TTF-1在气管食管瘘发育中的瘘管上皮中表达保守。尽管瘘管不形成次级分支以发育成肺，但TTF-1在瘘管中的表达模式反映了发育中肺的大气道中的表达。
气管食管瘘中的瘘管是一种源自呼吸的结构，在其在前肠的整个发育过程中表达肺特异性转录因子TTF-1。与它通常在发育中的肺中所起的模式形成作用相反，TTF-1不会诱导瘘管中的分支形态发生。因此，瘘管的非分支生长模式可能归因于局部间充质-上皮相互作用，这种相互作用超越了TTF-1的模式形成活性。
