NEDL2 is an essential regulator of enteric neural development and GDNF/Ret signaling

Cell Signal. 2015 Mar;27(3):578-86. doi: 10.1016/j.cellsig.2014.12.013. Epub 2014 Dec 30.

Abstract

Although glial cell line-derived neurotrophic factor (GDNF)/Ret signaling is essential for enteric nervous system (ENS) development, the positive regulators regulating GDNF/Ret signaling and controlling ENS development are poorly understood. Here, we show that Nedd4-related E3 ubiquitin ligase-2 (NEDL2) plays an essential and positive physiological role in regulating ENS development and GDNF/Ret signaling. All of the NEDL2-deficient mice die within 2weeks after birth, showing low body weight. These mice showed a progressive bowel motility defect resulting from intestinal aganglionosis. We show that NEDL2 positively regulates enteric neural precursor proliferation through the GDNF/Akt signaling pathway. Together, these findings unveil the physiological function of NEDL2 in vivo.

Keywords: Enteric nervous system; GDNF/Ret signaling; Mouse; NEDL2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Glial Cell Line-Derived Neurotrophic Factor / genetics
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism*
  • Intestines / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-ret / metabolism*
  • Signal Transduction*
  • Ubiquitin-Protein Ligases / deficiency
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Glial Cell Line-Derived Neurotrophic Factor
  • Hecw2 protein, mouse
  • Ubiquitin-Protein Ligases
  • Proto-Oncogene Proteins c-ret
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3