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: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=615933
• 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.

器官形成依赖于多个细胞过程，这些过程意味着由细胞-细胞接触或分泌的配体介导的旁分泌信号传导。如何解释信号指令以最终控制细胞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通路构成了参与细胞增殖、分化和存活的严格控制的主要通路。它转导许多生长因子的作用，这些生长因子与几种生物体中的细胞命运决定有关。在哺乳动物中，细胞外信号调节激酶ERK 1和ERK 2被双特异性（丝氨酸/苏氨酸和酪氨酸）激酶MEK 1和MEK 2激活。MEK 1和MEK 2在发育过程中的信号转导中起着重要而独特的作用。Mek 1功能的丧失导致胚胎在妊娠中期死亡，这是由于胎盘的生长和形态发生缺陷，而Mek 2突变小鼠不呈现表型。使用Mek 1条件等位基因和谱系特异性Cre小鼠品系，我们已经表明，MEK 1和MEK 2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力所必需的，揭示了ERK/MAPK级联在整个生命中的广泛作用。当MEK功能在上皮中被特异性消融时，发生胃肠（GI）缺陷，伴有肛门直肠畸形和小肠缩短。肠上皮细胞的增殖和分化也受到损害。肠上皮细胞呈现与CDX 2表达丧失相关的其顶膜的特异性延伸，表明细胞极性异常。最后，干细胞标志物的表达增加，表明干细胞龛中的扰动。总之，这些数据强调了ERK/MAPK通路在肠上皮中的重要性。我们推测ERK/MAPK级联反应在消化道器官发生和稳态过程中是至关重要的。我们研究计划的中心目标是研究参与肠道发育和细胞行为的ERK/MAPK通路驱动的遗传和分子机制，以阐明Mek 1和Mek 2基因如何协调胃肠道形态发生。为了实现这些目标，我们建议定义ERK/MAPK途径的作用： 1.在胃肠道上皮细胞的增殖和分化。 2.在肠上皮细胞极性中。 3.在维持肠上皮干细胞的生态位。