Lysophosphatidic Acid Signaling May Initiate Fetal Hydrocephalus

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Science Translational Medicine  07 Sep 2011:
Vol. 3, Issue 99, pp. 99ra87
DOI: 10.1126/scitranslmed.3002095

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Is the Cause of Hydrocephalus Blood Simple?

Hydrocephalus or “water on the brain” is caused by accumulation of cerebrospinal fluid (CSF) in the cerebral ventricles during fetal development and is one of the most common neurological disorders of newborns, occurring in 1 in 1500 live births. One apparent cause of hydrocephalus is bleeding into the cerebral ventricles or brain tissue of the fetus, suggesting that factors or components in blood may trigger development of this severe neurological disorder. The most common treatment is surgical insertion of an intraventricular shunt that drains excess CSF from the cerebral ventricles, but this approach only relieves intracranial pressure and does not solve the root cause of the disorder. Yung et al. set out to investigate which factors in blood trigger hydrocephalus using an in vivo fetal mouse model that they developed. They identify a blood-borne lipid called lysophosphatidic acid (LPA) as a potential cause of hydrocephalus and show that when LPA is prevented from binding to its receptor LPA1 by a receptor antagonist, that hydrocephalus does not develop in fetal mice.

The authors injected serum, plasma, or red blood cells into the cerebral ventricles of the brains of fetal mice in utero at 13.5 days of gestation. The animals were then assessed prenatally 1 or 5 days later or postnatally at several different time points. Injection of serum or plasma but not red blood cells induced CSF accumulation and hydrocephalus, with animals displaying enlarged heads, dilated ventricles, and thinning of the cortex. The investigators reasoned that LPA, a blood-borne lipid that is known to be important for the developing cerebral cortex, might be involved in the development of hydrocephalus. When they injected a solution containing LPA into the cerebral ventricles of fetal mice in utero, the mice did indeed develop severe hydrocephalus. The authors wondered how an increase in LPA might affect cortical development and lead to hydrocephalus. They show that injection of LPA resulted in altered adhesion and mislocalization of neural progenitor cells along the surface of the ventricles and that this mislocalization depended on expression of the LPA1 receptor by these cells. When the researchers repeated their experiments with fetal mice lacking the LPA1 receptor, they were unable to induce hydrocephalus. The key finding came with their demonstration that an LPA1 receptor antagonist blocked the ability of LPA to induce hydrocephalus in the fetal mice. These results suggest that LPA and its LPA1 receptor may be new therapeutic targets for developing drugs that could be used in conjunction with surgery to treat this debilitating neurological disease.


  • * Present address: Gunma Kokusai Academy, 1361-4 Uchigashima-cho, Ota, Gunma 373-0813, Japan.

  • Present address: Department of Pharmacology, College of Pharmacy, Gachon University of Medicine and Science, Incheon 406-799, Korea.

  • Present address: Department of Biology, Indiana University, Bloomington, IN 47401, USA.

  • Citation: Y. C. Yung, T. Mutoh, M.-E. Lin, K. Noguchi, R. R. Rivera, J.W. Choi, M. A. Kingsbury, J. Chun, Lysophosphatidic Acid Signaling May Initiate Fetal Hydrocephalus. Sci. Transl. Med. 3, 99ra87 (2011).

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