C-Type Natriuretic Peptide is a Schwann Cell-Derived Factor For Development and Function of Sensory Neurones
C-Type Natriuretic Peptide is a Schwann Cell-Derived Factor For Development and Function of Sensory Neurones
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DOI：
10.1111/j.1365-2826.2008.01778.x
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发表时间：
2008-11-01
影响因子：
3.2
通讯作者：
Kangawa, K.
中科院分区：
文献类型：
--
作者：
Kishimoto, I.;Tokudome, T.;Kangawa, K.
环GMP （cGMP）在神经元发育和神经突寻路中起重要作用。然而，神经系统中cGMP合成的调控机制尚不明确。在本研究中，我们研究了c型利钠肽（CNP）在周围神经系统中的作用，它可以通过与其受体，guanyyl环化酶(GC)-B结合而增加细胞内cGMP。免疫组化结果显示，CNP在雪旺细胞中表达，而GC-B mRNA在背根神经节（DRG）神经元中高表达。在培养的DRG神经元中，GC-B存在于trka阳性细胞的树突中，与cGMP依赖性蛋白激酶I （cGKI）共存，后者是cGMP作用的主要细胞内介质。在培养基中添加CNP增加了细神经突的密度，这伴随着血管扩张剂刺激磷酸化蛋白（一种cGKI底物）的磷酸化增加。此外，在缺乏CNP基因（CNP- ko）的小鼠中，trka阳性DRG神经元的数量减少。同样，CNP-KO小鼠DRG中cgki阳性神经元和脊髓背侧cgki阳性纤维也明显少于野生型小鼠。最后，与野生型相比，骨骼畸形修复的CNP-KO小鼠对福尔马林引起的疼痛的反应降低。综上所述，这些结果表明CNP来源于雪旺细胞，并在伤害感觉神经元的发育和功能中起重要作用。
Cyclic GMP (cGMP) is known to play important roles for neuronal development and neurite pathfinding. However, the regulatory mechanism that governs the synthesis of cGMP in the nervous system is not well defined. In the present study, we examined the role of C-type natriuretic peptide (CNP), which increases intracellular cGMP upon binding to its receptor, guanylyl cyclase (GC)-B, in the peripheral nervous system. Immunohistochemistry revealed that CNP is demonstrated in Schwann cells, whereas GC-B mRNA is highly expressed in dorsal root ganglion (DRG) neurones. In cultured DRG neurones, GC-B was demonstrated in dendrites of TrkA-positive cells, where it co-exists with cGMP-dependent protein kinase I (cGKI), the major intracellular mediator of cGMP actions. Addition of CNP in the culture medium increased the density of fine neurites, which was accompanied by the increase in phosphorylation of vasodilator-stimulated phosphoprotein, a cGKI substrate. Furthermore, in mice deficient for the CNP gene (CNP-KO), the numbers of TrkA-positive DRG neurones were diminished. Likewise, there were much less cGKI-positive neurones in DRG and cGKI-positive fibres in the dorsal spinal cord of CNP-KO than wild-type mice. Finally, the bone deformity-rescued CNP-KO mice displayed a decreased response to formalin-induced pain compared to wild-type. Taken together, these results suggest that CNP is derived from Schwann cells and plays an important role for the development and function of nociceptive sensory neurones.