The brain is composed of cells having distinct genomic DNA sequences that arise post-zygotically, known as somatic genomic mosaicism (SGM). One form of SGM is aneuploidy—the gain and/or loss of chromosomes—which is associated with mitotic spindle defects. The mitotic spindle orientation determines cleavage plane positioning and, therefore, neural progenitor cell (NPC) fate during cerebral cortical development. Here we report receptor-mediated signaling by lysophosphatidic acid (LPA) as a novel extracellular signal that influences cleavage plane orientation and produces alterations in SGM by inducing aneuploidy during murine cortical neurogenesis. LPA is a bioactive lipid whose actions are mediated by six G protein-coupled receptors, LPA1–LPA6. RNAscope and qPCR assessment of all six LPA receptor genes, and exogenous LPA exposure in LPA receptor (Lpar)-null mice, revealed involvement of Lpar1 and Lpar2 in the orientation of the mitotic spindle. Lpar1 signaling increased non-vertical cleavage in vivo by disrupting cell–cell adhesion, leading to breakdown of the ependymal cell layer. In addition, genomic alterations were significantly increased after LPA exposure, through production of chromosomal aneuploidy in NPCs. These results identify LPA as a receptor-mediated signal that alters both NPC fate and genomes during cortical neurogenesis, thus representing an extracellular signaling mechanism that can produce stable genomic changes in NPCs and their progeny. Normal LPA signaling in early life could therefore influence both the developing and adult brain, whereas its pathological disruption could contribute to a range of neurological and psychiatric diseases, via long-lasting somatic genomic alterations.

中文翻译：

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小鼠大脑皮层神经祖细胞中受体介导的溶血磷脂酸 (LPA) 信号传导产生的基因组非整倍性增加，从而改变切割面方向

大脑由具有不同基因组 DNA 序列的细胞组成，这些细胞在合子后出现，称为体细胞基因组嵌合 (SGM)。SGM 的一种形式是非整倍体——染色体的增加和/或丢失——与有丝分裂纺锤体缺陷有关。有丝分裂纺锤体方向决定了卵裂平面的定位，因此决定了大脑皮层发育过程中神经祖细胞 (NPC) 的命运。在这里，我们报告了溶血磷脂酸 (LPA) 受体介导的信号传导，作为一种新的细胞外信号，它影响切割平面方向，并通过在小鼠皮质神经发生过程中诱导非整倍体来产生 SGM 的改变。LPA 是一种生物活性脂质，其作用由六个 G 蛋白偶联受体 LPA1–LPA6 介导。所有六个 LPA 受体基因的 RNAscope 和 qPCR 评估，LPA 受体 (Lpar) 缺失小鼠中的外源 LPA 暴露表明 Lpar1 和 Lpar2 参与有丝分裂纺锤体的方向。Lpar1 信号通过破坏细胞间粘附来增加体内的非垂直切割，导致室管膜细胞层的分解。此外，通过在 NPC 中产生染色体非整倍体，LPA 暴露后基因组改变显着增加。这些结果表明 LPA 是一种受体介导的信号，可以在皮质神经发生过程中改变 NPC 的命运和基因组，从而代表一种细胞外信号机制，可以在 NPC 及其后代中产生稳定的基因组变化。因此，生命早期的正常 LPA 信号会影响发育中和成人的大脑，