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J. Biol. Chem., Vol. 282, Issue 39, 28768-28778, September 28, 2007

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Transcriptional Control of Cholesterol Biosynthesis in Schwann Cells by Axonal Neuregulin 1^*

Maria Pertusa¹², Cruz Morenilla-Palao¹³, Christelle Carteron², Felix Viana, and Hugo Cabedo⁴

From the Instituto de Neurociencias de Alicante, UMH-CSIC and Unidad de Investigación del Hospital de Sant Joan d'Alacant, 03550 Sant Joan, Alicante, Spain

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.

Received for publication, March 5, 2007 , and in revised form, July 25, 2007.

^* This work was supported in part by Spanish Ministry of Education and Science Grant SAF2004-01011 (to F. V.), "Instituto de Salud Carlos III" Grant PI05/0535, and "Conselleria de Salut de la Generalitat Valenciana" Grant AP-002/06 (to H. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Supported by predoctoral fellowships from the Spanish Ministry of Education and Science.

³ Supported by the postdoctoral program of the "Instituto de Salud Carlos III" from the Spanish Ministry of Health.

⁴ To whom correspondence should be addressed. E-mail: hugo.cabedo{at}umh.es.

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