Jung James, Frump Derek, Su Jared, Wang Weiping, Mozaffar Tahseen, Gupta Ranjan
Department of Orthopaedic Surgery, University of California, Irvine, CA 92697, USA.
Department of Orthopaedic Surgery, University of California, Irvine, CA 92697, USA; Department of Neurology, University of California, Irvine, CA 92697, USA.
Exp Neurol. 2015 Sep;271:84-94. doi: 10.1016/j.expneurol.2015.04.014. Epub 2015 May 1.
The secreted protein desert hedgehog (dhh) controls the formation of the nerve perineurium during development and is a key component of Schwann cells that ensures peripheral nerve survival. We postulated that dhh may play a critical role in maintaining myelination and investigated its role in demyelination-induced compression neuropathies by using a post-natal model of a chronic nerve injury in wildtype and dhh(-/-) mice. We evaluated demyelination using electrophysiological, morphological, and molecular approaches. dhh transcripts and protein are down-regulated early after injury in wild-type mice, suggesting an intimate relationship between the hedgehog pathway and demyelination. In dhh(-/-) mice, nerve injury induced more prominent and severe demyelination relative to their wild-type counterparts, suggesting a protective role of dhh. Alterations in nerve fiber characteristics included significant decreases in nerve conduction velocity, increased myelin debris, and substantial decreases in internodal length. Furthermore, in vitro studies showed that dhh blockade via either adenovirus-mediated (shRNA) or pharmacological inhibition both resulted in severe demyelination, which could be rescued by exogenous Dhh. Exogenous Dhh was protective against this demyelination and maintained myelination at baseline levels in a custom in vitro bioreactor to applied biophysical forces to myelinated DRG/Schwann cell co-cultures. Together, these results demonstrate a pivotal role for dhh in maintaining myelination. Furthermore, dhh signaling reveals a potential target for therapeutic intervention to prevent and treat demyelination of peripheral nerves in compression neuropathies.
分泌蛋白沙漠刺猬因子（dhh）在发育过程中控制神经束膜的形成，是雪旺细胞的关键组成部分，可确保周围神经的存活。我们推测dhh可能在维持髓鞘形成中起关键作用，并通过使用野生型和dhh（-/-）小鼠的慢性神经损伤产后模型研究其在脱髓鞘性压迫性神经病中的作用。我们使用电生理、形态学和分子方法评估脱髓鞘情况。野生型小鼠受伤后早期dhh转录本和蛋白表达下调，提示刺猬因子信号通路与脱髓鞘之间存在密切关系。在dhh（-/-）小鼠中，相对于野生型同窝小鼠，神经损伤诱导了更明显和严重的脱髓鞘，提示dhh具有保护作用。神经纤维特征的改变包括神经传导速度显著降低、髓鞘碎片增加以及节间长度大幅缩短。此外，体外研究表明，通过腺病毒介导（shRNA）或药理学抑制阻断dhh均导致严重脱髓鞘，外源性Dhh可挽救这种情况。外源性Dhh对这种脱髓鞘具有保护作用，并在定制的体外生物反应器中对施加生物物理力的有髓背根神经节/雪旺细胞共培养物中使髓鞘形成维持在基线水平。总之，这些结果证明dhh在维持髓鞘形成中起关键作用。此外，dhh信号揭示了一个潜在的治疗干预靶点，可用于预防和治疗压迫性神经病中周围神经的脱髓鞘。
