Transcriptional control of cholesterol biosynthesis in Schwann cells by axonal neuregulin 1.
A characteristic feature of many vertebrate axons is their wrapping by a lamellar stack of glially derived membranes known as the myelin sheath. Myelin is a cholesterol-rich membrane that allows for rapid saltatory nerve impulse conduction. Axonal neuregulins instruct glial cells on when and how much myelin they should produce. However, how neuregulin regulates myelin sheath development and thickness is unknown. Here we show that neuregulin receptors are activated by drops in plasma membrane cholesterol, suggesting that they can sense sterol levels. In Schwann cells neuregulin-1 increases the transcription of the 3-hydroxy-3-methylglutarylcoenzyme A reductase, the rate-limiting enzyme for cholesterol biosynthesis. Neuregulin activity is mediated by the phosphatidylinositol 3-kinase pathway and a cAMP-response element located on the reductase promoter. We propose that by activating neuregulin receptors, neurons exploit a cholesterol homeostatic mechanism forcing Schwann cells to produce new membranes for the myelin sheath. We also show that a strong phylogenetic correlation exists between myelination and cholesterol biosynthesis, and we propose that the absence of the sterol branch of the mevalonate pathway in invertebrates precluded the myelination of their nervous system.
Pertusa
Maria
M
Instituto de Neurociencias de Alicante, UMH-CSIC, 03550 Sant Joan, Alicante, Spain.
Morenilla-Palao
Cruz
C
Instituto de Neurociencias de Alicante, UMH-CSIC, 03550 Sant Joan, Alicante, Spain.
Carteron
Christelle
C
Instituto de Neurociencias de Alicante, UMH-CSIC, 03550 Sant Joan, Alicante, Spain.
Viana
Felix
F
Instituto de Neurociencias de Alicante, UMH-CSIC, 03550 Sant Joan, Alicante, Spain.
Cabedo
Hugo
H
Instituto de Neurociencias de Alicante, UMH-CSIC, 03550 Sant Joan, Alicante, Spain; Unidad de Investigación del Hospital de Sant Joan d'Alacant, 03550 Sant Joan, Alicante, Spain. Electronic address: hugo.cabedo@umh.es.
D000818:Animals; D001369:Axons / Q000201:enzymology; D019556:COS Cells; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000096:biosynthesis* / Q000235:genetics; D000242:Cyclic AMP / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000502:physiology; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis*; D008798:Mevalonic Acid / Q000378:metabolism; D009186:Myelin Sheath / Q000201:enzymology*; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000494:pharmacology*; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020218:Response Elements / Q000502:physiology; D015290:Second Messenger Systems / Q000187:drug effects* / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology
D002784:Cholesterol; D000242:Cyclic AMP; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; C094131:NRG1 protein, human