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

ERK/MAPK 通路在肠道发育和稳态中的作用

• 批准号: RGPIN-2016-05837
• 负责人: Charron, Jean
• 金额: $ 2.26万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=708548
• 关键词: Role; ERK; MAPK; pathway; intestine

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.

器官的形成依赖于多个细胞过程，这些过程意味着细胞-细胞接触或分泌的配体介导的旁分泌信号。如何解释信号指令以最终控制细胞的命运和形态发生是生物学中的一个中心问题。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通路是严密调控细胞增殖、分化和存活的主要途径。它传递了许多生长因子的作用，这些生长因子在几种生物中决定了细胞的命运。在哺乳动物中，细胞外信号调节的激酶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。MEK1功能的丧失导致胚胎死亡，原因是胎盘的生长和形态发生缺陷，而MEK2突变小鼠不表现出表型。使用MEK1条件等位基因和谱系特异的Cre小鼠品系，我们已经证明MEK1和MEK2都是正确的神经发生、皮肤形成、淋巴细胞生成、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级联信号通路在一生中的广泛作用。当MEK功能在上皮中被特定地消融时，胃肠道(GI)缺陷就会发生，并伴有肛门直肠畸形和小肠缩短。肠上皮的增殖和分化也受到损害。肠上皮细胞出现特殊的顶膜延伸，伴随CDX2表达的丧失，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干扰。总之，这些数据强调了ERK/MAPK通路在肠道上皮细胞中的重要性。我们假设ERK/MAPK级联信号通路在肠道器官发生和内稳态过程中对于传递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的形态发生。为了实现这些目标，我们建议定义ERK/MAPK通路的作用： 1.在胃肠上皮细胞的增殖和分化中。 2.肠上皮细胞的极性。 3.在维持肠上皮干细胞生态位方面。