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Lysophosphatidic acid (LPA) signaling in the etiology of detal hydrocephalus


Lysophosphatidic acid (LPA) is a small, ubiquitous phospholipid that acts as an extracellular signaling molecule through at least six cognate G protein-coupled receptors LPA₁₋₆. These receptors mediate diverse biological responses, including developmental, physiological, and pathophysiological effects. The embryonic nervous system is a major site of LPA presence and action through its receptors, although the precise cellular and mechanistic roles are not well understood. To study the role of LPA signaling in an intact developing cortex, I developed an in utero injection paradigm targeting mouse brain and used histology and immunochemistry in combination with pharmacological perturbation and LPA receptor null mutants to study this system. Overactivation of LPA₁ via a single LPA bolus exposure causes disruption of neuroprogenitor cells (NPCs) residing in the ventricular zone of the fetal brain, numerous accompanying histological changes - including ventricular dilation, formation of neurorosettes and heterotopias, mitotic displacement, loss of ependymal cells, ciliary defects, and 3rd ventricular occlusion - and subsequently fetal hydrocephalus (FH). In addition, exposure to blood derivatives and components such as serum and plasma through hemorrhage, two major sources of LPA, also cause FH. This modeled disorder can be prevented using both LPA₁ null mutants and pharmacological antagonism. This novel role of LPA in the etiology of FH is consistent with multiple, independent hydrocephalic models and clinical observations, suggesting common mechanistic pathways and, importantly, potential therapeutic targets for the amelioration of this disorder

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