Role of the ERK/MAPK pathway in intestine development and homeostasis

器官的形成依赖于多种细胞过程，包括由细胞间接触或分泌配体介导的旁分泌信号。如何解释信号指令最终控制细胞命运和形态发生是生物学中的一个核心问题。丝裂原活化蛋白激酶（MAPK）信号通路通过跨膜受体参与信号转导。ERK/MAPK通路是紧密控制细胞增殖、分化和存活的主要通路。它介导了许多生长因子的影响，这些因子与几种生物体中细胞命运的决定有关。在哺乳动物中，细胞外信号调节激酶ERK1和ERK2被双特异性（丝氨酸/苏氨酸和酪氨酸）激酶MEK1和MEK2激活。在发育过程中，MEK1和MEK2在信号转导中发挥着重要而独特的作用。由于胎盘生长和形态发生缺陷，Mek1功能的丧失导致妊娠中期胚胎死亡，而Mek2突变小鼠不表现出表型。利用Mek1条件等位基因和谱系特异性Cre小鼠系，我们发现Mek1和MEK2都是正确的神经发生、皮肤形成、淋巴生成、红细胞生成、肺和肾脏发育以及男性生育所必需的，揭示了ERK/MAPK级联在整个生命过程中的广泛作用。当MEK功能在上皮中特异性消融时，胃肠道（GI）缺陷发生，包括肛肠畸形和小肠缩短。肠上皮的增殖和分化也受到损害。肠细胞呈现出与CDX2表达缺失相关的顶膜特异性延伸，表明细胞极性异常。最后，干细胞标记物的表达增加，表明干细胞生态位受到扰动。总之，这些数据强调了ERK/MAPK通路在肠上皮中的重要性。我们假设ERK/MAPK级联在肠道器官发生和体内平衡过程中传导指导性信号是必不可少的。我们的研究计划的中心目标是研究由ERK/MAPK通路驱动的参与肠道发育和细胞行为的遗传和分子机制，以阐明Mek1和Mek2基因如何协调胃肠道形态发生。为了达到这些目标，我们建议定义ERK/MAPK通路的作用：***1。胃肠道上皮细胞的增殖和分化。* * * 2。肠上皮细胞极性。* * * 3。在肠上皮干细胞生态位的维持中的作用

Organ formation relies on multiple cellular processes that imply paracrine signaling mediated by cell-cell contacts or secreted ligands. How signal instructions are interpreted to ultimately control cell fate and morphogenesis is a central question in biology. The mitogen-activated protein kinase (MAPK) signaling pathways are involved in signal transduction through transmembrane receptors. The ERK/MAPK pathway constitutes the major pathway involved in the tight control of cell proliferation, differentiation and survival. It transduces the effects of many growth factors implicated in cell fate determination in several organisms. In mammals, the extracellular-signal-regulated kinases ERK1 and ERK2 are activated by the dual-specificity (serine/threonine and tyrosine) kinases MEK1 and MEK2. MEK1 and MEK2 played crucial and unique role in signal transduction during development. The loss of Mek1 function results in embryonic death at mid-gestation due to defects in growth and morphogenesis of the placenta whereas Mek2 mutant mice do not present phenotype. Using a Mek1 conditional allele and lineage-specific Cre mouse lines, we have shown that both MEK1 and MEK2 are required for correct neurogenesis, skin formation, lymphopoiesis, erythropoiesis, lung and kidney development and male fertility, revealing the broad role of the ERK/MAPK cascade throughout life. When MEK function is specifically ablated in the epithelium, gastrointestinal (GI) defects occur with anorectal malformations and small intestine shortening. The proliferation and differentiation of the intestinal epithelium is also compromised. The enterocytes present a specific extension of their apical membrane associated with the loss of CDX2 expression indicating abnormal cell polarity. Finally, expression of stem cell markers was increased suggesting perturbations in the stem cell niche. Altogether, these data underscore the importance of the ERK/MAPK pathway in intestinal epithelium. We hypothesize that the ERK/MAPK cascade is essential to transduce instructive signals during gut organogenesis and homeostasis. The central objective of our research program is to investigate the genetic and molecular mechanisms driven by the ERK/MAPK pathway that are involved in gut development and cell behavior in order to elucidate how Mek1 and Mek2 genes coordinate GI tract morphogenesis. To reach these goals, we propose to define the role of the ERK/MAPK pathway: ***1. In gastrointestinal epithelial cell proliferation and differentiation. ***2. In enterocyte cell polarity. ***3. In the maintenance of the intestinal epithelial stem cell niche.**