Reg-2 Is a Motoneuron Neurotrophic Factor and a Signalling Intermediate in the CNTF Survival Pathway

Nat Cell Biol. 2000 Dec;2(12):906-14. doi: 10.1038/35046558.

Abstract

Cytokines that are related to ciliary neurotrophic factor (CNTF) are physiologically important survival factors for motoneurons, but the mechanisms by which they prevent neuronal cell death remain unknown. Reg-2/PAP I (pancreatitis-associated protein I), referred to here as Reg-2, is a secreted protein whose expression in motoneurons during development is dependent on cytokines. Here we show that CNTF-related cytokines induce Reg-2 expression in cultured motoneurons. Purified Reg-2 can itself act as an autocrine/paracrine neurotrophic factor for a subpopulation of motoneurons, by stimulating a survival pathway involving phosphatidylinositol-3-kinase, Akt kinase and NF-kappaB. Blocking Reg-2 expression in motoneurons using Reg-2 antisense adenovirus specifically abrogates the survival effect of CNTF on cultured motoneurons, indicating that Reg-2 expression is a necessary step in the CNTF survival pathway. Reg-2 shows a unique pattern of expression in late embryonic spinal cord: it is progressively upregulated in individual motoneurons on a cell-by-cell basis, indicating that only a fraction of motoneurons in a given motor pool may be exposed to cytokines. Thus, Reg-2 is a neurotrophic factor for motoneurons, and is itself an obligatory intermediate in the survival signalling pathway of CNTF-related cytokines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium-Binding Proteins / antagonists & inhibitors
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / pharmacology
  • Calcium-Binding Proteins / physiology*
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • Ciliary Neurotrophic Factor / physiology*
  • Cytokines / physiology
  • Embryonic and Fetal Development / genetics
  • Embryonic and Fetal Development / physiology
  • Gene Expression Regulation, Developmental
  • Lithostathine
  • Motor Neurons / cytology
  • Motor Neurons / drug effects
  • Motor Neurons / physiology*
  • Nerve Growth Factors / antagonists & inhibitors
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / pharmacology
  • Nerve Growth Factors / physiology*
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / pharmacology
  • Nerve Tissue Proteins / physiology*
  • Pancreatitis-Associated Proteins
  • Rats
  • Signal Transduction

Substances

  • Calcium-Binding Proteins
  • Ciliary Neurotrophic Factor
  • Cytokines
  • Lithostathine
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Pancreatitis-Associated Proteins
  • REG3A protein, human
  • Reg1a protein, rat