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Molecular and Cellular Biology, December 2005, p. 11113-11121, Vol. 25, No. 24
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.24.11113-11121.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Essential Role for Sphingosine Kinases in Neural and Vascular Development

Kiyomi Mizugishi,1 Tadashi Yamashita,1 Ana Olivera,2 Georgina F. Miller,3 Sarah Spiegel,4 and Richard L. Proia1*

Genetics of Development and Disease Branch, NIDDK,1 Molecular Immunology and Inflammation Branch, NIAMS,2 Division of Veterinary Resources, National Institutes of Health, Bethesda, Maryland 20892,3 Department of Biochemistry, Virginia Commonwealth University School of Medicine, Richmond, Virginia 232984

Received 8 August 2005/ Returned for modification 10 September 2005/ Accepted 1 October 2005

Sphingosine-1-phosphate (S1P), an important sphingolipid metabolite, regulates diverse cellular processes, including cell survival, growth, and differentiation. Here we show that S1P signaling is critical for neural and vascular development. Sphingosine kinase-null mice exhibited a deficiency of S1P which severely disturbed neurogenesis, including neural tube closure, and angiogenesis and caused embryonic lethality. A dramatic increase in apoptosis and a decrease in mitosis were seen in the developing nervous system. S1P1 receptor-null mice also showed severe defects in neurogenesis, indicating that the mechanism by which S1P promotes neurogenesis is, in part, signaling from the S1P1 receptor. Thus, S1P joins a growing list of signaling molecules, such as vascular endothelial growth factor, which regulate the functionally intertwined pathways of angiogenesis and neurogenesis. Our findings also suggest that exploitation of this potent neuronal survival pathway could lead to the development of novel therapeutic approaches for neurological diseases.

* Corresponding author. Mailing address: Genetics of Development and Disease Branch, NIDDK, National Institutes of Health, Bldg. 10, Rm. 9N-314, 10 Center Dr., MSC 1821, Bethesda, MD 20892-1821. Phone: (301) 496-4391. Fax: (301) 496-0839. E-mail: proia{at}nih.gov.

Molecular and Cellular Biology, December 2005, p. 11113-11121, Vol. 25, No. 24
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.24.11113-11121.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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