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

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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.