Reg-2 is a motoneuron neurotrophic factor and a signalling intermediate in the CNTF survival pathway.
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.
Nishimune
H
H
INSERM U.382, IBDM (CNRS - INSERM - Université de la Méditerranée), Campus de Luminy - Case 907, 13288 Marseille Cedex 9, France.
Vasseur
S
S
Wiese
S
S
Birling
M C
MC
Holtmann
B
B
Sendtner
M
M
Iovanna
J L
JL
Henderson
C E
CE
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
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