Abstract
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.
Highlights
The vertebrate brain is composed of cells having distinct genomes that produce a complex genomic mosaic, which appears to arise at multiple points of brain development and maturity, including amongst neural progenitor cells (NPCs) during neurogenesis [1, 2]
lysophosphatidic acid (LPA) receptor signaling modulates cleavage plane orientation of apical progenitors in vivo We hypothesized that LPA exposure during development may alter the cleavage plane of NPCs prior to neurogenesis
Cleavage plane orientation was classified based on the angle of orientation relative to the ventricular surface, such that the cells fell into three groups: vertical (60o–90o), oblique (30o–60o), and horizontal (0o–30o) (Fig. 1a–c)
Summary
The vertebrate brain is composed of cells having distinct genomes that produce a complex genomic mosaic, which appears to arise at multiple points of brain development and maturity, including amongst neural progenitor cells (NPCs) during neurogenesis [1, 2]. “Non-vertical” oblique or horizontal cleavage plane orientation occurs just prior to neurogenesis when RGPs differentiate into intermediate progenitors or NPCs [6, 9, 11, 12]. This asymmetric, non-vertical cleavage is highly correlated with neurogenic division [6, 9, 11, 12] and leads to an increase in neuronal differentiation [3,4,5,6,7,8]
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