Edg-2 in myelin-forming cells: Isoforms, genomic mapping, and exclusion in Charcot-Marie-Tooth disease

Abstract

Edg‐2 is an heptahelical receptor whose spatio‐temporal distribution during rat brain development is consistent with a role in the control of myelination. We have now identified two splice variants of Edg‐2 mRNA in rat brain that encode two receptor isoforms differing by a stretch of 18 amino acids in the NH2‐terminal extracellular tail of the receptor. Prenatally (i.e., before oligodendrocyte myelination), the two variants detected by selective in situ hybridization are equally abundant, vary in parallel, and remain restricted to proliferative zones in the brain. Postnatally, the long isoform becomes predominant in myelinating structures, where its abundance increases sharply during the period of myelination. In the adult human brain, only the long variant was detected, while in situ hybridization showed it selectively expressed in the white matter and in clusters of cells showing features of oligodendrocytes of the temporal cerebral cortex. Consequently, the human Edg‐2 gene was studied to assess its possible contribution in inherited neuropathies. The coding sequence was found to be contained in three exons and to map to chromosome 9q31.3–32 by using radiation hybrid panel and Yeast‐Artificial Chromosomes. Two intragenic bi‐allelic polymorphisms and a rare mutation were identified. As a first application to molecular genetic studies, they were used to exclude the Edg‐2 gene in six families with phenotype of demyelinating Charcot‐Marie‐Tooth disease of unknown origin. GLIA 26:176–185, 1999. © 1999 Wiley‐Liss, Inc.

Edg8/S1P5: An Oligodendroglial Receptor with Dual Function on Process Retraction and Cell Survival

“…In a similar manner, LPA has been shown to induce retraction of processes in immature, but not mature, CG4 oligodendroglial cell lines and OPCs (Dawson et al, 2003), an effect that is likely mediated by the Edg2/LPA1 receptor (Allard et al, 1998(Allard et al, , 1999. It is of note that in the same study, Dawson et al (2003) reported that in addition to LPA, S1P also induced process retraction of undifferentiated CG4 cells.…”

“…The functional changes in the effect of Edg8/S1P5 activation may therefore relate to changes in receptor coupling with heterotrimeric G-proteins. This could occur by a variety of potential mechanisms including developmental switches of G-protein expression (i.e., from G12/13 to G␣ expression) or alternative splicing of the Edg8/S1P5 receptor resulting in changes to the coupling efficiency of the receptor to specific G-proteins, as suggested for Edg2/LPA1 (Allard et al, 1999). However, we were unable to isolate an alternative spliced variant of Edg8/S1P5 by comparison of RNA extracted from O4 ϩ -enriched pre-oligodendrocytes and mature oligodendrocytes (our unpublished data).…”

Characterization of lpa2 (Edg4) and lpa1/lpa2 (Edg2/Edg4) Lysophosphatidic Acid Receptor Knockout Mice: Signaling Deficits without Obvious Phenotypic Abnormality Attributable to lpa2

“…Mice lacking the lpa 1 gene [lpa 1 (Ϫ/Ϫ) knockout mice] were expected to have nervous system defects, because lpa 1 is abundantly expressed in progenitor cells of the embryonic cerebral cortex and myelinating glial cells of both the peripheral and central nervous systems (1,2,24,38,39). Indeed, the most severe phenotype of lpa 1 (Ϫ/Ϫ) mice was approximately 50% neonatal lethality due to defective suckling, attributable to defective olfaction (14).…”

“…The lpa 2 gene was the second such gene iden-tified, initially through sequence similarity searches using the lpa 1 sequence (3,11). Expression of the mouse lpa 2 transcript was found to be most abundant in kidney, testis, and embryonic brain, with low levels found in numerous other organs (13). When the LPA 2 receptor was expressed in mammalian cells, it mediated many of the same responses to LPA as LPA 1 (4,27), suggesting a functional redundancy in cells that express both receptors.…”

“…Thus, it was expected that lpa 1 (Ϫ/Ϫ) lpa 2 (Ϫ/Ϫ) double knockout mice would display much more severe phenotypes than lpa 1 (Ϫ/Ϫ) single knockout mice. Here we describe the generation and phenotype of lpa 2 (Ϫ/Ϫ) single and lpa 1…”