Loverde Joseph R, Tolentino Rosa E, Soteropoulos Patricia, Pfister Bryan J
Department of Biomedical Engineering, Center for Injury Biomechanics, Materials, and Medicine, New Jersey Institute of Technology, Newark, NJ, United States.
Department of Microbiology, Biochemistry and Molecular Genetics, Genomics Center, Rutgers New Jersey Medical School, Rutgers University, Newark, NJ, United States.
Front Neurosci. 2020 Dec 8;14:600136. doi: 10.3389/fnins.2020.600136. eCollection 2020.
At birth, there are 100 billion neurons in the human brain, with functional neural circuits extending through the spine to the epidermis of the feet and toes. Following birth, limbs and vertebrae continue to grow by several orders of magnitude, forcing established axons to grow by up to 200 cm in length without motile growth cones. The leading regulatory paradigm suggests that biomechanical expansion of mitotic tissue exerts tensile force on integrated nervous tissue, which synchronizes ongoing growth of spanning axons. Here, we identify unique transcriptional changes in embryonic rat DRG and cortical neurons while the corresponding axons undergo physiological levels of controlled mechanical stretch . Using bioreactors containing cultured neurons, we recapitulated the peak biomechanical increase in embryonic rat crown-rump-length. Biologically paired sham and "stretch-grown" DRG neurons spanned 4.6- and 17.2-mm in length following static or stretch-induced growth conditions, respectively, which was associated with 456 significant changes in gene transcription identified by genome-wide cDNA microarrays. Eight significant genes found in DRG were cross-validated in stretch-grown cortical neurons by qRT-PCR, which included upregulation of , , and downregulation of The results herein establish a link between biomechanics and gene transcription in mammalian neurons, which elucidates the mechanism underlying long-term growth of axons, and provides a basis for new research in therapeutic axon regeneration.
出生时，人类大脑中有1000亿个神经元，功能性神经回路从脊髓延伸至足部和脚趾的表皮。出生后，四肢和椎骨持续生长几个数量级，迫使已有的轴突在没有运动生长锥的情况下生长至200厘米长。主要的调控范式表明，有丝分裂组织的生物力学扩张对整合的神经组织施加拉力，从而使跨越轴突的持续生长同步。在此，我们确定了胚胎大鼠背根神经节（DRG）和皮质神经元中独特的转录变化，而相应的轴突经历了可控机械拉伸的生理水平。使用含有培养神经元的生物反应器，我们重现了胚胎大鼠顶臀长度生物力学增加的峰值。在静态或拉伸诱导的生长条件下，生物学配对的假手术组和“拉伸生长”的DRG神经元分别生长至4.6毫米和17.2毫米长，这与全基因组cDNA微阵列鉴定出的456个基因转录的显著变化相关。通过qRT-PCR在拉伸生长的皮质神经元中对DRG中发现的8个显著基因进行了交叉验证，其中包括 、 的上调和 的下调。本文的结果建立了哺乳动物神经元生物力学与基因转录之间的联系，阐明了轴突长期生长的潜在机制，并为治疗性轴突再生的新研究提供了基础。
