Roberts D J, Smith D M, Goff D J, Tabin C J
Departments of Pathology, Brigham and Women's Hospital and Massachusetts General Hospital, and Harvard Medical School, Fruit Street, Boston, MA 02114, USA.
Development. 1998 Aug;125(15):2791-801. doi: 10.1242/dev.125.15.2791.
The development of the vertebrate gut requires signaling between the endoderm and mesoderm for establishing its normal anteroposterior (AP) axis and for tissue-specific differentiation. Factors implicated in positional specification of the AP regions of the gut include endodermally expressed Sonic hedgehog (Shh), mesodermally expressed Bmp4 and members of the Hox gene family. We have investigated the roles of these factors during AP regional specification of the chick embryonic gut. Early in gut development, the endoderm sends inductive signals to the mesoderm. Shh has been implicated as one of these signals. We find a differential response to exposure of the inductive influence of Shh along the AP axis of the gut. Virally mediated misexpression of Shh results in ectopic upregulation of its receptor Ptc and a cellular proliferation throughout the gut mesoderm. Although ectopic Shh can induce Bmp4 in the mesoderm of the midgut and hindgut, Bmp4 is not induced in the stomach region of the foregut. The stomach region has a thicker layer of mesoderm than the rest of the gut suggesting that the normal function of Bmp4 could be to limit mesodermal growth in the non-stomach regions of the gut. Ectopic Bmp4 expression in the stomach results in a reduction of the mesodermal component consistent with this hypothesis. In addition to the regional restriction on Bmp4 induction, Shh can only induce Hoxd-13 in the mesoderm of the hindgut. These findings suggest that a prepattern exists in the primitive gut mesoderm prior to expression of Shh in the endoderm. The gut mesoderm is subsequently responsible for inducing region-specific differentiation of its overlying endoderm. We tested the role of Hoxd-13, normally restricted in its mesodermal expression to the most posterior region of the hindgut (cloaca), in controlling adjacent endodermal differentiation. When virally mediated Hoxd-13 is misexpressed in the primitive midgut mesoderm, there is a transformation of the endoderm to the morphology and mucin content of the hindgut. Thus, the positionally restricted expression of a Hox gene in the gut mesoderm influences the inductive signaling that leads to regionally specific differentiation of gut endoderm.
脊椎动物肠道的发育需要内胚层和中胚层之间的信号传导，以建立其正常的前后（AP）轴并实现组织特异性分化。与肠道AP区域位置特化相关的因素包括内胚层表达的音猬因子（Shh）、中胚层表达的Bmp4以及Hox基因家族的成员。我们研究了这些因子在鸡胚肠道AP区域特化过程中的作用。在肠道发育早期，内胚层向中胚层发送诱导信号。Shh被认为是这些信号之一。我们发现，沿肠道AP轴对Shh诱导作用的暴露存在差异反应。病毒介导的Shh错误表达导致其受体Ptc的异位上调以及整个肠道中胚层的细胞增殖。虽然异位Shh可在中肠和后肠的中胚层中诱导Bmp4，但在前肠的胃区域中不诱导Bmp4。胃区域的中胚层层比肠道其他部位厚，这表明Bmp4的正常功能可能是限制肠道非胃区域的中胚层生长。胃中异位Bmp4表达导致中胚层成分减少，这与该假设一致。除了对Bmp4诱导的区域限制外，Shh仅能在后肠的中胚层中诱导Hoxd-13。这些发现表明，在内胚层中Shh表达之前，原始肠道中胚层中存在一种预模式。随后，肠道中胚层负责诱导其上方内胚层的区域特异性分化。我们测试了通常在中胚层表达中局限于后肠最末端区域（泄殖腔）的Hoxd-13在控制相邻内胚层分化中的作用。当病毒介导的Hoxd-13在原始中肠中胚层中错误表达时，内胚层会转变为后肠的形态和黏蛋白含量。因此，肠道中胚层中Hox基因的位置受限表达会影响诱导信号传导，并导致肠道内胚层的区域特异性分化。
