Shh及其受体Ptc和Smo在胚胎期小鼠5-HT能尾端缝核核团及缝核脊髓束表达特点的研究
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摘要
中枢神经系统有许多能传导特定信息的神经通路,这些神经通路通过轴突传导某种特定信息,如运动、视、听或感觉信息等。按神经信息的传导方向,神经通路可分为上行和下行两种。下行神经通路主要是由脑中的神经核团发出轴突并向脊髓尾端方向投射。缝核脊髓束(Raphespinal Tract, RST)是一条重要的下行神经通路,它由脑干的尾端缝核核团(Caudal Raphe Nuclei, CRN)发出并向脊髓尾端投射。因这些核团分泌5-羟色胺(5-HT)神经递质,故又称5-HT能神经元。我们以前的研究发现,5-HT能神经轴突在小鼠E11.5天时从CRN发出,E12.5-E16.5天,RST沿脊髓腹外侧投射至脊髓最尾端。Sonic hedgehog (Shh)是一种形成素,广泛参与胚胎期多种神经元的发育,主要表达在脊髓的底板,并可分泌到整个腹侧脊髓,调控脊髓腹侧神经元的发育。近年的研究表明,Shh也是一种神经轴突导向分子,控制一些神经轴突在发育期间的定向投射。本研究中,我们运用分子原位杂交技术,发现Shh mRNA表达在E12.5-E14.5天小鼠脊髓腹侧底板,并随着RST向尾端的投射而呈现出从头端到尾端梯度递减的表达特点。免疫组织化学法发现,Shh的受体Patched (Ptc)和Smoothened (Smo)也随着RST的投射而呈现出同的表达特点。E11.5天,Ptc在5-HT能CRN表达,但Smo却几乎不表达。E12.5-E14.5天,Ptc和Smo在5-HT能CRN及RST均有表达。我们的研究结果提示,Shh作为神经轴突导向分子,很有可能参与调控了5-HT能RST在脊髓中从头端向尾端的定向投射。
In the central nervous system, specific signals, such as motor, sensory, visual and auditory signals, are conducted by different nervous pathways. Raphespinal Tract (RST) is one of the most important descending nervous pathways, and its axons are originated from the caudal raphe nuclei (CRN) localized along the midline of the brain stem. The neurons in raphe nuclei are also called serotonergic neurons because they secrete neurotransmitter 5-hydroxytryptamine (5-HT). Our previous studies have found that serotonergic axons are originated from CRN at E11.5, and serotonergic RST axons descend through the ventral spinal cord from E12.5 to E16.5 in mice. Sonic hedgehog (Shh) is a kind of morphogen that is expressed in the floor plate of the spinal cord, and can be secreted to the whole ventral spinal cord at embryonic stages to regulate the development and migration of many neurons. Recent studies have shown that Shh also plays a role in guiding axons'directed projection as an axon guidance cue. In the present study, in situ hybridization or immunohistochemical method was employed to detect the expression patterns of Shh or its receptors patched (Ptc) and smoothened (Smo) along the anterior to posterior (A-P) axis of developing spinal cord. The expression of Shh could be detected in ventro-floor plate of the spinal cord of mice between E12.5 and E14.5, and showed a decrement expression pattern along the A-P axis as the projection progression of serotonergic RST to caudal end. The expression of Ptc could be detected in serotonergic CRN of mice at E1 1.5, however, the expression of Smo could not be detected at this stage. The expressions of both Ptc and Smo could be detected in serotonergic CRN and RST axons of mice between E12.5 and E14.5. Our findings strongly suggest that Shh, as an axon guidance cue, may be involved in guiding the serotonergic RST directed projection along the A-P axis of developing spinal cord.
In the central nervous system, specific signals, such as motor, sensory, visual and auditory signals, are conducted by different nervous pathways. Raphespinal Tract (RST) is one of the most important descending nervous pathways, and its axons are originated from the caudal raphe nuclei (CRN) localized along the midline of the brain stem. The neurons in raphe nuclei are also called serotonergic neurons because they secrete neurotransmitter 5-hydroxytryptamine (5-HT). Our previous studies have found that serotonergic axons are originated from CRN at E11.5, and serotonergic RST axons descend through the ventral spinal cord from E12.5 to E16.5 in mice. Sonic hedgehog (Shh) is a kind of morphogen that is expressed in the floor plate of the spinal cord, and can be secreted to the whole ventral spinal cord at embryonic stages to regulate the development and migration of many neurons. Recent studies have shown that Shh also plays a role in guiding axons'directed projection as an axon guidance cue. In the present study, in situ hybridization or immunohistochemical method was employed to detect the expression patterns of Shh or its receptors patched (Ptc) and smoothened (Smo) along the anterior to posterior (A-P) axis of developing spinal cord. The expression of Shh could be detected in ventro-floor plate of the spinal cord of mice between E12.5 and E14.5, and showed a decrement expression pattern along the A-P axis as the projection progression of serotonergic RST to caudal end. The expression of Ptc could be detected in serotonergic CRN of mice at E1 1.5, however, the expression of Smo could not be detected at this stage. The expressions of both Ptc and Smo could be detected in serotonergic CRN and RST axons of mice between E12.5 and E14.5. Our findings strongly suggest that Shh, as an axon guidance cue, may be involved in guiding the serotonergic RST directed projection along the A-P axis of developing spinal cord.
引文
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9. J. Briscoe, L. Sussel, P. Serup, et al. Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling[J].Nature,1999,398(6728):622-7.
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16. A. Pattyn, A. Vallstedt, J.M. Dias, et al. Coordinated temporal and spatial control of motor neuron and serotonergic neuron generation from a common pool of CNS progenitors[J].Genes Dev,2003,17(6):729-37.
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19. T. Hendricks, N. Francis, D. Fyodorov, et al. The ETS domain factor Pet-1 is an early and precise marker of central serotonin neurons and interacts with a conserved element in serotonergic genes[J].J Neurosci,1999,19(23):10348-56.
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21. M.P. Smidt, C.H. Asbreuk, J.J. Cox, et al. A second independent pathway for development of mesencephalic dopaminergic neurons requires Lmxlb[J].Nat Neurosci,2000, 3(4):337-41.
22. L. Cheng, C.L. Chen, P. Luo, et al. Lmxlb, Pet-1, and Nkx2.2 coordinately specify serotonergic neurotransmitter phenotype[J].J Neurosci,2003,23(31):9961-7.
23. N. Rajaofetra, F. Sandillon, M. Geffard, et al. Pre-and post-natal ontogeny of serotonergic projections to the rat spinal cord[J].J Neurosci Res,1989,22(3):305-21.
24. B. Ballion, P. Branchereau, J. Chapron, et al. Ontogeny of descending serotonergic innervation and evidence for intraspinal 5-HT neurons in the mouse spinal cord[J].Brain Res Dev Brain Res,2002,137(1):81-8.
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27. M. Murone, A. Rosenthal and F.J. de Sauvage. Sonic hedgehog signaling by the patched-smoothened receptor complex[J].Curr Biol,1999,9(2):76-84.
28. J.K. Chen, J. Taipale, K.E. Young, et al. Small molecule modulation of Smoothened activity[J].Proc Natl Acad Sci USA,2002,99(22):14071-6.
29. M.J. Fietz, J.P. Concordet, R. Barbosa, et al. The hedgehog gene family in Drosophila and vertebrate development[J].Dev Suppl,1994,43-51.
30. R.D. Riddle, R.L. Johnson, E. Laufer, et al. Sonic hedgehog mediates the polarizing activity oftheZPA[J].Cell,1993,75(7):1401-16.
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