Department of Neuroscience, Tufts University School of Medicine, Boston, MA, 02111, USA.
Graduate School of Biomedical Sciences, Tufts University, Boston, MA, 02111, USA.
Nat Commun. 2023 Aug 24;14(1):5150. doi: 10.1038/s41467-023-40926-2.
Developing astroglia play important roles in regulating synaptogenesis through secreted and contact signals. Whether they regulate postnatal axon growth is unknown. By selectively isolating exosomes using size-exclusion chromatography (SEC) and employing cell-type specific exosome reporter mice, our current results define a secreted astroglial exosome pathway that can spread long-range in vivo and stimulate axon growth of cortical pyramidal neurons. Subsequent biochemical and genetic studies found that surface expression of glial HepaCAM protein essentially and sufficiently mediates the axon-stimulating effect of astroglial exosomes. Interestingly, apolipoprotein E (ApoE), a major astroglia-secreted cholesterol carrier to promote synaptogenesis, strongly inhibits the stimulatory effect of astroglial exosomes on axon growth. Developmental ApoE deficiency also significantly reduces spine density of cortical pyramidal neurons. Together, our study suggests a surface contact mechanism of astroglial exosomes in regulating axon growth and its antagonization by ApoE, which collectively coordinates early postnatal pyramidal neuronal axon growth and dendritic spine formation.
星形胶质细胞的发育在通过分泌和接触信号调节突触发生中发挥重要作用。它们是否调节出生后的轴突生长尚不清楚。通过使用大小排阻层析（SEC）选择性地分离外泌体，并使用细胞类型特异性外泌体报告小鼠，我们当前的结果定义了一种可在体内长距离传播并刺激皮质锥体神经元轴突生长的分泌型星形胶质细胞外泌体途径。随后的生化和遗传研究发现，神经胶质 HepaCAM 蛋白的表面表达基本上足以介导星形胶质细胞外泌体的轴突刺激作用。有趣的是，载脂蛋白 E (ApoE)，一种促进突触发生的主要星形胶质细胞分泌的胆固醇载体，强烈抑制星形胶质细胞外泌体对轴突生长的刺激作用。发育性 ApoE 缺乏也显著降低了皮质锥体神经元的棘突密度。总之，我们的研究表明星形胶质细胞外泌体在调节轴突生长及其与 ApoE 的拮抗作用中的表面接触机制，共同协调出生后早期锥体神经元轴突生长和树突棘形成。
