The role of lsc/p115-RhoGEF-regulated pathways for development and function of the enteric nervous system in the upper gastrointestinal tract.

• Applicant: Dr. Eugen Zizer
• Subject Area: Gastroenterology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2013 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 247486657

• Final Report Year: 2017

Final Report Abstract

In summary, we could demonstrate the essential role of lsc/p115-RhoGEF for the embryonic migration of glial cells and colonization of the upper GI-tract. We were able to show the direct connection between the proliferative activity of glial cells and the lsc/p115-RhoGEF-expression. For the first time the according signalling pathway could be evaluated in detail: the role of lsc/p115-RhoGEF-expression for the GDNF-associated stimulation of glial cells could be demonstrated. One of the most crucial signalling ways that was revealed was the ability of lsc/p115-RhoGEF to neutralize the antiproliferative effect of p53 with breakup of p53-caused cell cycle arrest in the G0/1-phase. Furthermore the proliferative effect of GDNF is strongly linked with JNK-activation and expression of Cyclin D3 and ppm1d. Furthermore the expression pattern of other RhoGEF-proteins was evaluated showing some potential compensating mechanisms (more-expression of intersectin2, ARHGEF2 and 9). Interestingly, the effect of lsc/p115-RhoGEF-expression seems to show some other characteristics, not described before, besides the proliferative effect in glial cells: lsc/p115-RhoGEF seems to show some anti-fibrosis protective effect in murine pancreas. In TGF-alphatransgenic animals lsc/p115-RhoGEF-KO results in amelioration of pro-fibrosis effect linked by TGF-alpha-overexpression. The expression of lsc/p115-RhoGEF in pancreatic stellate cells may play an important role for this connection.

Publications

• lsc/p115-RhoGEF beeinflusst die embryonale Entwicklung des murinen enterischen Nervensystems mit Entwicklung eines Achalasie-ähnlichen Phänotyps in der lsc/p115-RhoGEF-defizienten Maus. XXV. Kongress der südwestdeutschen Gesellschaft für Gastroenterologie 2014, Ulm
  Zizer E, Güthle M, Beilke S, Möhnle U, Wegele J, Groneberg D, Fischer KD, Seufferlein T, Wagner M
  
• lsc/p115-RhoGEF reguliert die embryonale Entwicklung des embryonalen enterischen Nervensystems des murinen enterischen Nervensystems mit Entwicklung eines Achalasie-ähnlichen Phänotyps in der lsc/p115-RhoGEF-defeizienten Maus. XXV. Kongress der südwestdeutschen Gesellschaft für Gastroenterologie 2014, Ulm
  Zizer E, Güthle M, Beilke S, Möhnle U, Wegele J, Groneberg D, Fischer KD, Seufferlein T, Wagner M
  
• lsc/p115-RhoGEF-Defizienz resultiert in einem signifikant geringeren Pankreas Fibrosegrad am Modell der TGFα-transgenen Maus. Jahrestagung der deutschen Gesellschaft für Verdauungs- und Stoffwechselerkrankungen 2015, Leipzig
  Zizer E, Bartz J, Güthle M, Möhnle U, Fischer KD, Seufferlein T, Wagner M
  (See online at https://dx.doi.org/10.1055/s-0035-1559083)
• Lsc/p115-RhoGEF ist erforderlich für die GDNF-vermittelte Proliferationsantwort der enterischen Gliazellen im murinen GI-Trakt. Jahrestagung der deutschen Gesellschaft für Verdauungs- und Stoffwechselerkrankungen 2016, Hamburg
  Zizer E, Bartz J, Güthle M, Möhnle U, Seufferlein T, Wagner M
  (See online at https://dx.doi.org/10.1055/s-0036-1587117)
• Achalasie: innovative Modelle und Verfahren für Verständnis, Diagnose und Therapie ösophagealer Motilitätsstörungen. Univ. Ulm, Habil. 2017. 45, 53 Bl.
  Zizer E