Lysophospholipid receptors LPA1–3 are not required for the inhibitory effects of LPA on mouse retinal growth cones

Abstract

One of the major requirements in the development of the visual system is axonal guidance of retinal ganglion cells toward correct targets in the brain. A novel class of extracellular lipid signaling molecules, lysophospholipids, may serve as potential axon guidance cues. They signal through cognate G protein-coupled receptors, at least some of which are expressed in the visual system. Here we show that in the mouse visual system, a lysophospholipid known as lysophosphatidic acid (LPA) is inhibitory to retinal neurites in vitro when delivered extracellularly, causing growth cone collapse and neurite retraction. This inhibitory effect of LPA is both active in the nanomolar range and specific compared to the related lysophospholipid, sphingosine 1-phosphate (S1P). Knockout mice lacking three of the five known LPA receptors, LPA1–3, continue to display retinal growth cone collapse and neurite retraction in response to LPA, demonstrating that these three receptors are not required for these inhibitory effects and indicating the existence of one or more functional LPA receptors expressed on mouse retinal neurites that can mediate neurite retraction.

G-Protein-Coupled Receptor Cell Signaling Pathways Mediating Embryonic Chick Retinal Growth Cone Collapse Induced by Lysophosphatidic Acid and Sphingosine-1-Phosphate

“…In comparison to the mouse system, we note some differences between this current study on chick and our previous study on mouse [19]. First, in chick, both LPA and S1P cause retinal growth cone collapse, while in mouse, S1P does not cause retinal growth cone collapse, only LPA.…”

“…Could they be involved in axon guidance? This work and others has demonstrated that the lysophospholipids LPA and S1P cause growth cone collapse in a variety of cell types, including RGCs [16,19,22]. Growth cone collapse is a hallmark of an inhibitory axon guidance cue.…”

“…We are investigating a novel set of biologically active molecules, signaling lysophospholipids, specifically lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P), as potential axon guidance cues. Similar to well-documented, inhibitory guidance cues, LPA and S1P have been shown to cause growth cone collapse in culture in a variety of neuronal cell lines [10–15] and some primary neurons [16,17, 18], including mouse and Xenopus retinal axons [19–22]. Furthermore, there is evidence in Xenopus that S1P may be involved in correct pathfinding into the tectum [22].…”

Lysophospholipids and their receptors in the central nervous system

“…In postmitotic neurons, LPA-induced morphological changes cannot be completely explained by LPA 1 , LPA 2 , and LPA 3 [51,83]. LPA-induced neurite retraction is accompanied by the formation of F-actin filament retraction fiber caps in postmitotic cortical neurons where two LPA receptors, LPA 1 and LPA 2 , are expressed [51].…”

“…The effects were preserved even in LPA 1 -deficient cortical neurons [51]. Recently, another report showed that LPA 1 , LPA 2 , and LPA 3 do not appear required to induce morphological changes in retinal neurons in response to LPA [83]. LPA induces neurite retraction and growth cone collapse in retinal neurons, which is preserved in cells lacking LPA 1 , LPA 2 , and LPA 3 [83].…”