title: Reg-2 is a motoneuron neurotrophic factor and a signalling intermediate in the CNTF survival pathway.
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.
authors.affiliation: INSERM U.382, IBDM (CNRS - INSERM - Université de la Méditerranée), Campus de Luminy - Case 907, 13288 Marseille Cedex 9, France.
authors.forename: H
authors.initials: H
authors.lastname: Nishimune
authors.forename: S
authors.initials: S
authors.lastname: Vasseur
authors.forename: S
authors.initials: S
authors.lastname: Wiese
authors.forename: M C
authors.initials: MC
authors.lastname: Birling
authors.forename: B
authors.initials: B
authors.lastname: Holtmann
authors.forename: M
authors.initials: M
authors.lastname: Sendtner
authors.forename: J L
authors.initials: JL
authors.lastname: Iovanna
authors.forename: C E
authors.initials: CE
authors.lastname: Henderson
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor / Q000502:physiology*; D016207:Cytokines / Q000502:physiology; D005314:Embryonic and Fetal Development / Q000235:genetics / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D051847:Lithostathine; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D000073718:Pancreatitis-Associated Proteins; D051381:Rats; D015398:Signal Transduction
chemical_list: D002135:Calcium-Binding Proteins; D020934:Ciliary Neurotrophic Factor; D016207:Cytokines; D051847:Lithostathine; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; C497616:Reg1a protein, rat