Abstract
The neural-crest-derived sympathoadrenal cell lineage gives rise to sympathetic neurons and to endocrine chromaffin cells of the adrenal medulla. Both cell types express a largely overlapping set of genes, including those coding for the molecular machinery related to the synthesis and exocytotic release of catecholamines. During their early development, sympathetic neurons and chromaffin cells rely on a shared transcription factor network that controls the establishment of these common features. Despite many similarities, mature sympathetic neurons and chromaffin cells significantly differ regarding their morphology and function. Most prominently, sympathetic neurons possess axons that are absent in mammalian adrenal chromaffin cells. The molecular mechanism underlying the divergent development of sympathoadrenal cells into neuronal and endocrine cells remains elusive. Mutational inactivation of the ribonuclease dicer hints at the importance of microRNAs in this diversification. We show here that miR-124 is detectable in developing sympathetic neurons but absent in chromaffin cell precursors. We further demonstrate that miR-124 promotes neurite elongation when transfected into cultured chromaffin cells indicating its capability to support the establishment of a neuronal morphology in non-neuronal sympathoadrenal cells. Our results also show that treatment of PC12 cells with the neurotrophin nerve growth factor leads to an upregulation of miR-124 expression and that inhibition of miR-124 reduces nerve-growth-factor-induced neurite outgrowth in PC12 cells. Thus, our data indicate that miR-124 contributes to the establishment of specific neuronal features in developing sympathoadrenal cells.
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Åkerblom M, Sachdeva R, Barde I, Verp S, Gentner B, Trono D, Jakobsson J (2012) MicroRNA-124 is a subventricular zone neuronal fate determinant. J Neurosci 32:8879–8889. doi:10.1523/JNEUROSCI.0558-12.2012
Bernstein E, Caudy AA, Hammond SM, Hannon GJ (2001) Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409:363–366. doi:10.1038/35053110
Cao X, Pfaff SL, Gage FH (2007) A functional study of miR-124 in the developing neural tube. Genes Dev 21:531–536. doi:10.1101/gad.1519207
Cheng L-C, Pastrana E, Tavazoie M, Doetsch F (2009) miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nat Neurosci 12:399–408. doi:10.1038/nn.2294
Cuellar TL, Davis TH, Nelson PT, Loeb GB, Harfe BD, Ullian E, McManus MT (2008) Dicer loss in striatal neurons produces behavioral and neuroanatomical phenotypes in the absence of neurodegeneration. Proc Natl Acad Sci U S A 105:5614–5619. doi:10.1073/pnas.0801689105
Davis N, Mor E, Ashery-Padan R (2011) Roles for Dicer1 in the patterning and differentiation of the optic cup neuroepithelium. Development 138:127–138. doi:10.1242/dev.053637
Ernsberger U, Patzke H, Rohrer H (1997) The developmental expression of choline acetyltransferase (ChAT) and the neuropeptide VIP in chick sympathetic neurons: evidence for different regulatory events in cholinergic differentiation. Mech Dev 68:115–126
Greene LA, Tischler AS (1976) Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor.Proc Natl Acad Sci U S A 73:2424–2428
Guo H, Ingolia NT, Weissman JS, Bartel DP (2010) Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466:835–840. doi:10.1038/nature09267
Gut P, Huber K, Lohr J, Brühl B, Oberle S, Treier M, Ernsberger U, Kalcheim C, Unsicker K (2005) Lack of an adrenal cortex in Sf1 mutant mice is compatible with the generation and differentiation of chromaffin cells. Development 132:4611–4619. doi:10.1242/dev.02052
Gu X, Meng S, Liu S, Jia C, Fang Y, Li S, Fu C, Song Q, Lin L, Wang X (2014) miR-124 represses ROCK1 expression to promote neurite elongation through activation of the PI3K/Akt signal pathway. J Mol Neurosci 52:156–165. doi:10.1007/s12031-013-0190-6
Harfe BD, McManus MT, Mansfield JH, Hornstein E, Tabin CJ (2005) The RNaseIII enzyme Dicer is required for morphogenesis but not patterning of the vertebrate limb. Proc Natl Acad Sci U S A 102:10898–10903. doi:10.1073/pnas.0504834102
Harris KS, Zhang Z, McManus MT, Harfe BD, Sun X (2006) Dicer function is essential for lung epithelium morphogenesis. Proc Natl Acad Sci U S A 103:2208–2213. doi:10.1073/pnas.0510839103
Hendrickson DG, Hogan DJ, McCullough HL, Myers JW, Herschlag D, Ferrell JE, Brown PO (2009) Concordant regulation of translation and mRNA abundance for hundreds of targets of a human microRNA. PLoS Biol 7:e1000238. doi:10.1371/journal.pbio.1000238
Huang T, Liu Y, Huang M, Zhao X, Cheng L (2010) Wnt1-cre-mediated conditional loss of Dicer results in malformation of the midbrain and cerebellum and failure of neural crest and dopaminergic differentiation in mice. J Mol Cell Biol 2:152–163. doi:10.1093/jmcb/mjq008
Huber K (2006) The sympathoadrenal cell lineage: specification, diversification, and new perspectives. Dev Biol 298:335–343. doi:10.1016/j.ydbio.2006.07.010
Huber K (2015) Segregation of neuronal and neuroendocrine differentiation in the sympathoadrenal lineage. Cell Tissue Res 359:333-341. doi:10.1007/s00441-014-1947-0
Huber K, Kalcheim C, Unsicker K (2009) The development of the chromaffin cell lineage from the neural crest. Auton Neurosci Basic Clin 151:10–16. doi:10.1016/j.autneu.2009.07.020
Kosik KS (2009) MicroRNAs tell an evo–devo story. Nat Rev Neurosci 10:754–759. doi:10.1038/nrn2713
Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T (2002) Identification of tissue-specific microRNAs from mouse. Curr Biol 12:735–739
Lee V, Trojanowski JQ, Schlaepfer WW (1982) Induction of neurofilament triplet proteins in PC12 cells by nerve growth factor. Brain Res 238:169–180
Makeyev EV, Zhang J, Carrasco MA, Maniatis T (2007) The microRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Mol Cell 27:435–448. doi:10.1016/j.molcel.2007.07.015
Mathonnet G, Fabian MR, Svitkin YV, Parsyan A, Huck L, Murata T, Biffo S, Merrick WC, Darzynkiewicz E, Pillai RS, Filipowicz W, Duchaine TF, Sonenberg N (2007) MicroRNA inhibition of translation initiation in vitro by targeting the cap-binding complex eIF4F. Science 317:1764–1767. doi:10.1126/science.1146067
McManus MT, Sharp PA (2002) Gene silencing in mammals by small interfering RNAs. Nat Rev Genet 3:737–747. doi:10.1038/nrg908
Nagalakshmi VK, Ren Q, Pugh MM, Valerius MT, McMahon AP, Yu J (2011) Dicer regulates the development of nephrogenic and ureteric compartments in the mammalian kidney. Kidney Int 79:317–330. doi:10.1038/ki.2010.385
Ogawa M, Ishikawa T, Ohta H (1986) Transdifferentiation of endocrine chromaffin cells into neuronal cells. Curr Top Dev Biol 20:99–110
Rohrer H (2011) Transcriptional control of differentiation and neurogenesis in autonomic ganglia. Eur J Neurosci 34:1563–1573. doi:10.1111/j.1460-9568.2011.07860.x
Schimmelpfeng J, Weibezahn K-F, Dertinger H (2004) Quantification of NGF-dependent neuronal differentiation of PC-12 cells by means of neurofilament-L mRNA expression and neuronal outgrowth. J Neurosci Methods 139:299–306. doi:10.1016/j.jneumeth.2004.05.010
Shtukmaster S, Schier MC, Huber K, Krispin S, Kalcheim C, Unsicker K (2013) Sympathetic neurons and chromaffin cells share a common progenitor in the neural crest in vivo. Neural Dev 8:12. doi:10.1186/1749-8104-8-12
Stappert L, Borghese L, Roese-Koerner B, Weinhold S, Koch P, Terstegge S, Uhrberg M, Wernet P, Brüstle O (2013) MicroRNA-based promotion of human neuronal differentiation and subtype specification. PLoS ONE 8:e59011. doi:10.1371/journal.pone.0059011
Stubbusch J, Narasimhan P, Huber K, Unsicker K, Rohrer H, Ernsberger U (2013) Synaptic protein and pan-neuronal gene expression and their regulation by Dicer-dependent mechanisms differ between neurons and neuroendocrine cells. Neural Dev 8:16. doi:10.1186/1749-8104-8-16
Thermann R, Hentze MW (2007) Drosophila miR2 induces pseudo-polysomes and inhibits translation initiation. Nature 447:875–878. doi:10.1038/nature05878
Tiveron MC, Hirsch MR, Brunet JF (1996) The expression pattern of the transcription factor Phox2 delineates synaptic pathways of the autonomic nervous system. J Neurosci 16:7649–7660
Unsicker K, Krisch B, Otten U, Thoenen H (1978) Nerve growth factor-induced fiber outgrowth from isolated rat adrenal chromaffin cells: impairment by glucocorticoids. Proc Natl Acad Sci U S A 75:3498–3502
Vinores SA, Marangos PJ, Parma AM, Guroff G (1981) Increased levels of neuron-specific enolase in PC12 pheochromocytoma cells as a result of nerve growth factor treatment. J Neurochem 37:597–600
Visvanathan J, Lee S, Lee B, Lee JW, Lee SK (2007) The microRNA miR-124 antagonizes the anti-neural REST/SCP1 pathway during embryonic CNS development. Genes Dev 21:744–749. doi:10.1101/gad.1519107
Yu J-Y, Chung K-H, Deo M, Thompson RC, Turner DL (2008) MicroRNA miR-124 regulates neurite outgrowth during neuronal differentiation. Exp Cell Res 314:2618–2633. doi:10.1016/j.yexcr.2008.06.002
Zehir A, Hua LL, Maska EL, Morikawa Y, Cserjesi P (2010) Dicer is required for survival of differentiating neural crest cells. Dev Biol 340:459–467. doi:10.1016/j.ydbio.2010.01.039
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The authors thank Ute Baur and Ellen Gimbel for excellent technical assistance.
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Stella Shtukmaster, Priyanka Narasimhan and Tehani El Faitwri contributed equally to this work.
This work was supported by a grant from the DFG to H.R. and U.E. (RO469/12-1) and K.U. (UN 34/24-1).
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Shtukmaster, S., Narasimhan, P., El Faitwri, T. et al. MiR-124 is differentially expressed in derivatives of the sympathoadrenal cell lineage and promotes neurite elongation in chromaffin cells. Cell Tissue Res 365, 225–232 (2016). https://doi.org/10.1007/s00441-016-2395-9
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DOI: https://doi.org/10.1007/s00441-016-2395-9