Role of GDNF and Wnt/beta-catenin signaling in pancreas development and physiology
- Autores: José Luis Muñoz Bravo
- Directores de la Tesis: David Antonio Cano González (dir. tes.), Juan José Toledo Aral (tut. tes.)
- Lectura: En la Universidad de Sevilla ( España ) en 2016
- Idioma: inglés
- Número de páginas: 129
- Tribunal Calificador de la Tesis: Ricardo Pardal Redondo (presid.), Luis M. Escudero Cuadrado (secret.), Patricia Ybot González (voc.), Irene Cozar Castellano (voc.), David Macías Gutiérrez (voc.)
- Materias:
- Enlaces
- Tesis en acceso abierto en: Idus
- Resumen
The pancreas is of great medical relevance due to the devastating diseases associated with failure of this organ, including diabetes, pancreatitis and pancreatic cancer. Much of the molecular knowledge gained in pancreas development has also contributed to shed light on the mechanisms underlying adult organ homeostasis and metaplasia. Thus, it has become increasingly evident that many of the embryonic signaling pathways involved in pancreas development also play crucial roles in pancreas regeneration and cancer in the adult organism. Furthermore, the application of developmental lessons to beta-cell differentiation protocols from stem cells have positioned the cell therapy as a promising goal to restore normoglycemia in diabetic patients.
This work took advantage of the combined use of genetically engineered mice, genomic, histopathology and molecular and cellular biology techniques to analyze the role of GDNF and Wnt/canonical signaling in pancreas development GDNF is required for neural colonization of the pancreas During embryonic development, neural crest cells migrating in a rostrocaudal direction populate the gut, giving rise to neural progenitor cells. Recent studies in mice have shown that neural crest cells enter the pancreatic epithelium at E11.5. However, the cues that guide the migration of neural progenitors into the pancreas are poorly defined. In this study we identify glial cell line-derived neurotrophic factor (GDNF) as a key player in this process. GDNF displays a dynamic expression pattern during embryonic development that parallels the chronology of migration and differentiation of neural crest derivatives in the pancreas. Conditional inactivation of Gdnf in the pancreatic epithelium results in a dramatic loss of neuronal and glial cells and in reduced parasympathetic innervation in the pancreas. Importantly, the innervation of other regions of the gut remains unaffected. Analysis of Gdnf mutant mouse embryos and ex vivo experiments indicate that GDNF produced in the pancreas acts as a neurotrophic factor for gut-resident neural progenitor cells. Our data further show that exogenous GDNF promotes the proliferation of pancreatic progenitor cells in organ culture. In summary, our results point to GDNF as crucial for the development of the intrinsic innervation of the pancreas.
Hyperactive Wnt signaling causes pancreatic hypoplasia by redirecting the developmental fate of embryonic pancreas towards a gastrointestinal identity Organ formation is achieved through the complex interplay between signaling pathways and transcriptional cascades. The Wnt/beta-catenin signaling pathway plays multiples roles during embryonic development including patterning, proliferation and differentiation in different tissues. Previous studies have established the importance of this pathway at multiple stages of pancreas formation as well as in postnatal organ function and homeostasis. Gain of function experiments in mice have demonstrated that activation of the Wnt/beta-catenin pathway results in pancreatic hypoplasia, a phenomenon whose underlying mechanisms remains to be elucidated. Here, we show that the activation of the Wnt/beta-catenin signaling in pancreatic progenitors causes a cell fate conversion towards the gastrointestinal lineage. We demonstrate that ectopic activation of epithelial beta-catenin causes aberrant induction of gastric and intestinal markers both in the pancreatic epithelium and mesenchyme, leading to the development of gut-like features. Furthermore, we provide evidence that beta-catenin-induced reprogramming of pancreatic progenitors into those of a gastrointestinal fate depends on Hedgehog signaling. Together, our data emphasize the developmental plasticity of pancreatic progenitors.
