Hlx homeo box gene is essential for an inductive tissue interaction that drives expansion of embryonic liver and gut
Hlx homeo box gene is essential for an inductive tissue interaction that drives expansion of embryonic liver and gut
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DOI：
10.1101/gad.10.1.70
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发表时间：
1996-01-01
影响因子：
10.5
通讯作者：
Harvey, RP
中科院分区：
文献类型：
--
作者：
Hentsch, B;Lyons, I;Harvey, RP
小鼠同源异型框基因Hlx的差异表达存在于特定的造血细胞类型中，并且在胚胎发生期间，显著表达于发育中的肝脏、胆囊和肠道的内脏间充质。对该基因的靶向破坏现已证实它在内脏器官发生中起关键作用。纯合突变的胚胎在胚胎第15天左右死亡，伴有贫血以及肝脏和肠道的严重发育不全。肝脏个体发育正常起始于肝憩室的形成和肝细胞的分化，但该器官未能扩张，仅达到正常大小的3%。明显的肝脏发育不全与凋亡细胞的显著增加无关。肠道发育也正常开始，但肠道未能进行广泛的伸长和盘曲，仅达到正常长度的四分之一。贫血是由于肝脏中发生的胎儿造血形式的缺陷所致，但在体外未观察到Hlx（-/-）造血细胞的内在缺陷，并且移植到受辐照的正常小鼠中的肝脏来源的Hlx（-/-）造血干细胞能够完全重建造血功能。因此，受损的胎儿造血反映了微小肝脏提供的支持功能不足。Hlx通常在位于受突变影响的发育中的肝脏和肠道上皮附近的内脏间充质中表达，但不在上皮本身表达。因此，Hlx调节一种间充质 - 上皮相互作用，这种相互作用驱动内脏器官发生中的一个关键生长阶段。此外，由于Hlx的突变阻止了肝脏生长，但不影响其特化、早期形态发生或分化，这个器官的发育似乎是在不同的遗传控制下通过逐步的诱导相互作用发生的。
The divergent murine homeo box gene Hlx is expressed in restricted hematopoietic cell types and, during embryogenesis, prominently in visceral mesenchyme of the developing liver, gall bladder, and gut. Targeted disruption of the gene has now established that it plays a key role in visceral organogenesis. Embryos homozygous for the mutation died around embryonic day 15 with anemia and severe hypoplasia of the liver and gut. Liver ontogeny commenced normally with formation of the liver diverticulum and differentiation of hepatocytes, but the organ failed to expand and reached only 3% of normal size. The apparent liver hypoplasia was not associated with a notable increase in apoptotic cells. Gut development also began normally but the intestines failed to undergo extensive elongation and leaping and reached only a quarter of normal length. The anemia resulted from a deficiency in the fetal form of hematopoiesis, which occurs in the liver, but no intrinsic defect in Hlx(-/-) hematopoietic cells was observed in vitro, and liver-derived Hlx(-/-) hematopoietic stem cells that were transplanted to irradiated normal mice could fully reconstitute hematopoiesis. The impaired fetal hematopoiesis therefore reflects insufficient support function provided by the minute liver. Hlx is normally expressed in visceral mesenchyme lying adjacent to the developing liver and gut epithelia affected by the mutation, but not in the epithelia themselves. Hence, Hlx regulates a mesenchymal-epithelial interaction that drives a vital growth phase in visceral organogenesis. Moreover, because mutation of Hlx blocked liver growth but not its specification, early morphogenesis, or differentiation, development of this organ appears to occur by step-wise inductive interactions under separate genetic control.