# LPA6 signaling as a modulator of oligodendrocyte differentiation and CNS myelination

> **NIH NIH R21** · VIRGINIA COMMONWEALTH UNIVERSITY · 2021 · $415,888

## Abstract

The vertebrate central nervous system (CNS) myelin sheath enables fast and efficient signal propagation along
axons, and it provides metabolic support for maintaining axonal integrity. With these features, the CNS myelin
sheath critically contributes to neuronal circuitry function. Thus, it may not appear surprising that dysregulation
of the transcriptional program governing the differentiation of the myelinating cells of the CNS, namely
oligodendrocytes (OLGs), emerges as significant contributor to the pathophysiology of an increasing number of
neurological diseases. Despite the critical importance of OLG differentiation for CNS function, however,
the signaling pathways regulating these events are still only poorly understood. In this context, receptors
with selectivity for the lipid signaling molecule lysophosphatidic acid (LPA) have long been known to be
expressed by OLGs but the functional roles of LPA signaling in regulating OLG differentiation have largely
remained obscure. One of the major pathways by which LPA is generated is via the enzymatic
lysophospholipase D (lyso PLD) activity of the extracellular protein autotaxin (ATX). Through our previous studies,
we established that inhibition of ATX’s lysoPLD activity attenuates OLG differentiation, thus suggesting a positive
modulatory role of LPA receptor signaling in OLG differentiation. To date, six bona fide LPA receptors (LPA1-6
encoded by Lpar1-6) have been recognized in mammals. With the exception of Lpar5, all of these receptors are,
at least to some extent, expressed by cells of the OLG lineage. In an effort to dissect the individual roles of the
known LPA receptors, our most recent findings point, somewhat surprisingly, toward a negative modulatory role
of signaling via LPA6. Notably, it has been shown that LPA6 receptor responses can be triggered by membrane-
embedded LPA generated via the enzymatic activity of membrane-associated Lipase H (LIPH), and transcriptional
profiling reveals that OLGs, especially at the earlier stages of the lineage, also express Liph. Collectively, these
observations support the central hypothesis that LPA6 signaling functions as a negative modulator of the
transcriptional program associated with OLG differentiation, whereby this signaling event is likely
triggered primarily by LIPH activity generated LPA. In the proposed studies, we will characterize 1) in vivo the
role of OLG-derived LPA6 in modulating developmental OLG differentiation and, thereby, CNS myelination via
the generation and analysis of conditional Lpar6 knockout mice, and 2) in vitro the role of LPA6 and Lipase H
(LIPH)-mediated LPA6 activation in OLG differentiation via the use of a well-established system of rat-derived
primary cultures of differentiating OLGs. Taken together, the proposed studies address the conceptually
novel idea that OLG differentiation and CNS myelination are regulated by a complex LPA signaling
network with opposing, i.e. positive and negative modulatory, componen...

## Key facts

- **NIH application ID:** 10288115
- **Project number:** 1R21NS123317-01
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** BABETTE FUSS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $415,888
- **Award type:** 1
- **Project period:** 2021-07-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10288115

## Citation

> US National Institutes of Health, RePORTER application 10288115, LPA6 signaling as a modulator of oligodendrocyte differentiation and CNS myelination (1R21NS123317-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10288115. Licensed CC0.

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