Ercan Ebru, Han Juliette M, Di Nardo Alessia, Winden Kellen, Han Min-Joon, Hoyo Leonie, Saffari Afshin, Leask Andrew, Geschwind Daniel H, Sahin Mustafa
Department of Neurology, F.M. Kirby Center for Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
J Exp Med. 2017 Mar 6;214(3):681-697. doi: 10.1084/jem.20160446. Epub 2017 Feb 9.
Disruption of myelination during development has been implicated in a range of neurodevelopmental disorders including tuberous sclerosis complex (TSC). TSC patients with autism display impairments in white matter integrity. Similarly, mice lacking neuronal have a hypomyelination phenotype. However, the mechanisms that underlie these phenotypes remain unknown. In this study, we demonstrate that neuronal TSC1/2 orchestrates a program of oligodendrocyte maturation through the regulated secretion of connective tissue growth factor (CTGF). We characterize oligodendrocyte maturation both in vitro and in vivo. We find that neuron-specific deletion results in an increase in CTGF secretion that non-cell autonomously stunts oligodendrocyte development and decreases the total number of oligodendrocytes. Genetic deletion of CTGF from neurons, in turn, mitigates the TSC-dependent hypomyelination phenotype. These results show that the mechanistic target of rapamycin (mTOR) pathway in neurons regulates CTGF production and secretion, revealing a paracrine mechanism by which neuronal signaling regulates oligodendrocyte maturation and myelination in TSC. This study highlights the role of mTOR-dependent signaling between neuronal and nonneuronal cells in the regulation of myelin and identifies an additional therapeutic avenue for this disease.
发育过程中髓鞘形成的破坏与一系列神经发育障碍有关，包括结节性硬化症（TSC）。患有自闭症的TSC患者在白质完整性方面存在缺陷。同样，缺乏神经元的小鼠具有髓鞘形成不足的表型。然而，这些表型背后的机制仍然未知。在本研究中，我们证明神经元中的TSC1/2通过调节结缔组织生长因子（CTGF）的分泌来协调少突胶质细胞成熟程序。我们在体外和体内对少突胶质细胞成熟进行了表征。我们发现神经元特异性缺失导致CTGF分泌增加，这非细胞自主地阻碍少突胶质细胞发育并减少少突胶质细胞总数。反过来，从神经元中基因删除CTGF可减轻TSC依赖的髓鞘形成不足表型。这些结果表明，神经元中的雷帕霉素机制性靶标（mTOR）途径调节CTGF的产生和分泌，揭示了一种旁分泌机制，通过该机制神经元信号传导调节TSC中的少突胶质细胞成熟和髓鞘形成。这项研究强调了mTOR依赖的神经元与非神经元细胞之间的信号传导在髓鞘调节中的作用，并确定了针对该疾病的另一条治疗途径。
