Non-proliferative effects of lysophosphatidic acid enhance cortical growth and folding

Abstract

Lysophosphatidic acid (LPA) is a phospholipid that has extracellular signaling properties mediated by G protein-coupled receptors. Two LPA receptors, LPA(1) and LPA(2), are expressed in the embryonic cerebral cortex, suggesting roles for LPA signaling in cortical formation. Here we report that intact cerebral cortices exposed to extracellular LPA ex vivo rapidly increased in width and produced folds resembling gyri, which are not normally present in mouse brains and are absent in LPA(1) LPA(2) double-null mice. Mechanistically, growth was not due to increased proliferation but rather to receptor-dependent reduced cell death and increased terminal mitosis of neural progenitor cells (NPCs). Our results implicate extracellular lipid signals as new influences on brain formation during embryonic development.

Rho/ROCK pathway is essential to the expansion, differentiation, and morphological rearrangements of human neural stem/progenitor cells induced by lysophosphatidic acid

“…In iPSC-derived NS/PCs, LPA also signifi cantly decreased proliferation, while a similar trend was observed in hESC-derived NS/PCs but without reaching statistical signifi cance. Hence, our data shows generally consistent results across different iPSC and hESC lines, with some minor interline differences in responsiveness to tiation of human iPSCs, which is in agreement with our previous study using hESCs ( 39 ) and with data obtained in rodents ( 58 ); although other studies found opposite effects in various NS/PCs and neuroblasts ( 14,17,18,38,59,60 ).…”

“…We found that LPA promoted apoptosis of early human NS/PCs, as revealed by neurosphere formation assay, which is consistent with some NS/PC and neuroblast studies performed in rodents ( 16,17,38,57,58 ) but differs with others in which LPA improves cell survival ( 16,38 ) or proliferation ( 13,35,59 ). In human cells, we previously showed that LPA does not modify apoptosis of older hESCderived NS/PCs ( 39 ) as, when two-week-old hESC-derived within minutes; Fig.…”

“…A large body of evidence shows that LPA acts through the Rho pathway to modify cell survival, apoptosis, and proliferation in diverse types of cells by mediating cell shape/focal adhesion alteration ( 38,69,70 ). Our current data demonstrate that LPA activates RhoA in human NS/PCs and implicate this pathway in LPA-induced apoptosis, decreased proliferation, and together with the PI3K/Akt pathway, LPA inhibition of neuronal differentiation of human NS/PCs.…”

“…It was recently shown that LPA can induce fetal hydrocephalus in the mouse by an aberrant activation of Lpa 1 on NS/PCs during development ( 19 ). LPA also acts through the Rho pathway to induce morphological rearrangements in neuroblasts and neurons (20)(21)(22)(23)(24), including actin polymerization ( 21 ) that leads to the formation of retraction fi bers, neurite retraction ( 21,(25)(26)(27)(28)(29)(30)(31)(32), cell rounding ( 26,29,33,34 ), cluster compaction (35)(36)(37)(38), and growth cone collapse ( 21,26,27 ).…”

Expression patterns of the lysophospholipid receptor genes during mouse early development

“…Mice deficient in each of the LPA or S1P receptor genes (excluding Lpa 4 , Lpa 5 , and S1p 4 ) have been reported, and double-or triple-knockout mice have been produced for Lpa 1-3 and S1p 1-3 (Contos et al, 2000Kingsbury et al, 2003;Ye et al, 2005Ye et al, , 2008Liu et al, 2000;MacLennan et al, 2001MacLennan et al, , 2006Kono et al, 2004Kono et al, , 2007Cinamon et al, 2004;Jaillard et al, 2005;Herr et al, 2007;Means et al, 2007). However, none of the genetically modified mice reported so far appear to exhibit apparent deficiencies in the formation of somites, possibly because of functional compensation or redundancy among LPA/S1P receptor genes.…”