In humans, neurosecretory chromaffin cells control a number of important bodily functions, including those related to stress response. Chromaffin cells appear as a distinct cell type at the beginning of midgestation and are the main cellular source of adrenalin and noradrenalin released into the blood stream. In mammals, two different chromaffin organs emerge at a close distance to each other, the adrenal gland and Zuckerkandl organ (ZO). These two structures are found in close proximity to the kidneys and dorsal aorta, in a region where paraganglioma, pheochromocytoma and neuroblastoma originate in the majority of clinical cases. Recent studies showed that the chromaffin cells comprising the adrenal medulla are largely derived from nerve-associated multipotent Schwann cell precursors (SCPs) arriving at the adrenal anlage with the preganglionic nerve fibers, whereas the migratory neural crest cells provide only minor contribution. However, the embryonic origin of the ZO, which differs from the adrenal medulla in a number of aspects, has not been studied in detail. The ZO is composed of chromaffin cells in direct contact with the dorsal aorta and the intraperitoneal cavity and disappears through an autophagy-mediated mechanism after birth. In contrast, the adrenal medulla remains throughout the entire life and furthermore, is covered by the adrenal cortex. Using a combination of lineage tracing strategies with nerve- and cell type-specific ablations, we reveal that the ZO is largely SCP-derived and forms in synchrony with progressively increasing innervation. Moreover, the ZO develops hand-in-hand with the adjacent sympathetic ganglia that coalesce around the dorsal aorta. Finally, we were able to provide evidence for a SCP-contribution to a small but significant proportion of sympathetic neurons of the posterior paraganglia. Thus, this cellular source complements the neural crest, which acts as a main source of sympathetic neurons. Our discovery of a nerve-dependent origin of chromaffin cells and some sympathoblasts may help to understand the origin of pheochromocytoma, paraganglioma and neuroblastoma, all of which are currently thought to be derived from the neural crest or committed sympathoadrenal precursors.

Center for Brain Research Medical University of Vienna Vienna Austria

Cold Spring Harbor Laboratory Cold Spring Harbor NY United States

Department of Experimental Biology Faculty of Science Masaryk University Brno Czechia

Department of Neuroscience Karolinska Institutet Stockholm Sweden

Department of Physiology and Pharmacology Karolinska Institutet Stockholm Sweden

Institute of Animal Physiology and Genetics CAS Brno Czechia

National Scientific Center of Marine Biology Far Eastern Branch Russian Academy of Sciences Vladivostok Russia

Unit of Molecular Neurobiology Department of Medical Biochemistry and Biophysics Karolinska Institutet Stockholm Sweden

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Adameyko I., Lallemend F., Aquino J. B., Pereira J. A., Topilko P., Muller T., et al. (2009). Schwann cell precursors from nerve innervation are a cellular origin of melanocytes in skin. Cell 139 366–379. 10.1016/j.cell.2009.07.049 PubMed DOI

Adameyko I., Lallemend F., Furlan A., Zinin N., Aranda S., Kitambi S. S., et al. (2012). Sox2 and Mitf cross-regulatory interactions consolidate progenitor and melanocyte lineages in the cranial neural crest. Development 139 397–410. 10.1242/dev.065581 PubMed DOI PMC

Allmendinger A., Stoeckel E., Saarma M., Unsicker K., Huber K. (2003). Development of adrenal chromaffin cells is largely normal in mice lacking the receptor tyrosine kinase c-Ret. Mech. Dev. 120 299–304. 10.1016/S0925-4773(02)00455-0 PubMed DOI

Altergott R., Barbato A., Lawrence A., Paloyan E., Freeark R. J., Prinz R. A. (1985). Spectrum of catecholamine-secreting tumors of the organ of Zuckerkandl. Surgery 98 1121–1126. PubMed

Böck P. (1982). “The paraganglia,” in Handbuch der mikroskopischen Anatomie des Menschen, Vol. VI, eds Oksche A., Vollrath L. (Berlin: Springer; ). 10.1007/978-3-642-68208-7 DOI

Britsch S., Goerich D. E., Riethmacher D., Peirano R. I., Rossner M., Nave K. A., et al. (2001). The transcription factor Sox10 is a key regulator of peripheral glial development. Genes Dev. 15 66–78. 10.1101/gad.186601 PubMed DOI PMC

Chan W. H., Gonsalvez D. G., Young H. M., Southard-Smith E. M., Cane K. N., Anderson C. R. (2016). Differences in CART expression and cell cycle behavior discriminate sympathetic neuroblast from chromaffin cell lineages in mouse sympathoadrenal cells. Dev. Neurobiol. 76 137–149. 10.1002/dneu.22304 PubMed DOI PMC

Coupland R. E. (1965). The Natural History of the Chromaffin Cell. Harlow: Longmans, Green and Co.

Dyachuk V., Furlan A., Shahidi M. K., Giovenco M., Kaukua N., Konstantinidou C., et al. (2014). Neurodevelopment. Parasympathetic neurons originate from nerve-associated peripheral glial progenitors. Science 345 82–87. 10.1126/science.1253281 PubMed DOI

Enomoto H., Crawford P. A., Gorodinsky A., Heuckeroth R. O., Johnson E. M., Jr., Milbrandt J. (2001). RET signaling is essential for migration, axonal growth and axon guidance of developing sympathetic neurons. Development 128 3963–3974. PubMed

Ernsberger U., Esposito L., Partimo S., Huber K., Franke A., Bixby J. L., et al. (2005). Expression of neuronal markers suggests heterogeneity of chick sympathoadrenal cells prior to invasion of the adrenal anlagen. Cell Tissue Res. 319 1–13. 10.1007/s00441-004-0996-1 PubMed DOI

Espinosa-Medina I., Outin E., Picard C. A., Chettouh Z., Dymecki S., Consalez G. G., et al. (2014). Neurodevelopment. Parasympathetic ganglia derive from Schwann cell precursors. Science 345 87–90. 10.1126/science.1253286 PubMed DOI

Fishbein L., Leshchiner I., Walter V., Danilova L., Robertson A. G., Johnson A. R., et al. (2017). Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell 31 181–193. 10.1016/j.ccell.2017.01.001 PubMed DOI PMC

Furlan A., Adameyko I. (2018). Schwann cell precursor: a neural crest cell in disguise? Dev. Biol. 10.1016/j.ydbio.2018.02.008 [Epub ahead ofprint]. PubMed DOI

Furlan A., Dyachuk V., Kastriti M. E., Calvo-Enrique L., Abdo H., Hadjab S., et al. (2017). Multipotent peripheral glial cells generate neuroendocrine cells of the adrenal medulla. Science 357:eaal3753. 10.1126/science.aal3753 PubMed DOI PMC

Furlan A., La Manno G., Lubke M., Haring M., Abdo H., Hochgerner H., et al. (2016). Visceral motor neuron diversity delineates a cellular basis for nipple- and pilo-erection muscle control. Nat. Neurosci. 19 1331–1340. 10.1038/nn.4376 PubMed DOI

Goebbels S., Oltrogge J. H., Kemper R., Heilmann I., Bormuth I., Wolfer S., et al. (2010). Elevated phosphatidylinositol 3,4,5-trisphosphate in glia triggers cell-autonomous membrane wrapping and myelination. J. Neurosci. 30 8953–8964. 10.1523/JNEUROSCI.0219-10.2010 PubMed DOI PMC

Guillemot F., Joyner A. L. (1993). Dynamic expression of the murine achaete-scute homologue Mash-1 in the developing nervous system. Mech. Dev. 42 171–185. 10.1016/0925-4773(93)90006-J PubMed DOI

Hirsch M. R., Tiveron M. C., Guillemot F., Brunet J. F., Goridis C. (1998). Control of noradrenergic differentiation and Phox2a expression by MASH1 in the central and peripheral nervous system. Development 125 599–608. PubMed

Hockman D., Adameyko I., Kaucka M., Barraud P., Otani T., Hunt A., et al. (2018). Striking parallels between carotid body glomus cell and adrenal chromaffin cell development. Dev. Biol. 10.1016/j.ydbio.2018.05.016 [Epub ahead of print]. PubMed DOI PMC

Huber K. (2006). The sympathoadrenal cell lineage: specification, diversification, and new perspectives. Dev. Biol. 298 335–343. 10.1016/j.ydbio.2006.07.010 PubMed DOI

Huber K., Bruhl B., Guillemot F., Olson E. N., Ernsberger U., Unsicker K. (2002a). Development of chromaffin cells depends on MASH1 function. Development 129 4729–4738. PubMed

Huber K., Combs S., Ernsberger U., Kalcheim C., Unsicker K. (2002b). Generation of neuroendocrine chromaffin cells from sympathoadrenal progenitors: beyond the glucocorticoid hypothesis. Ann. N. Y. Acad. Sci. 971 554–559. PubMed

Huber K., Janoueix-Lerosey I., Kummer W., Rohrer H., Tischler A. S. (2018). The sympathetic nervous system: malignancy, disease, and novel functions. Cell Tissue Res. 372 163–170. 10.1007/s00441-018-2831-0 PubMed DOI

Huber K., Kalcheim C., Unsicker K. (2009). The development of the chromaffin cell lineage from the neural crest. Auton. Neurosci. 151 10–16. 10.1016/j.autneu.2009.07.020 PubMed DOI

Isern J., Garcia-Garcia A., Martin A. M., Arranz L., Martin-Perez D., Torroja C., et al. (2014). The neural crest is a source of mesenchymal stem cells with specialized hematopoietic stem cell niche function. Elife 3:e03696. 10.7554/eLife.03696 PubMed DOI PMC

Jessen K. R., Mirsky R. (2005). The origin and development of glial cells in peripheral nerves. Nat. Rev. Neurosci. 6 671–682. 10.1038/nrn1746 PubMed DOI

Jessen K. R., Mirsky R., Salzer J. (2008). Introduction. schwann cell biology. Glia 56 1479–1480. 10.1002/glia.20779 PubMed DOI

Kaukua N., Shahidi M. K., Konstantinidou C., Dyachuk V., Kaucka M., Furlan A., et al. (2014). Glial origin of mesenchymal stem cells in a tooth model system. Nature 513 551–554. 10.1038/nature13536 PubMed DOI

Kobayashi K., Morita S., Sawada H., Mizuguchi T., Yamada K., Nagatsu I., et al. (1995). Targeted disruption of the tyrosine hydroxylase locus results in severe catecholamine depletion and perinatal lethality in mice. J. Biol. Chem. 270 27235–27243. 10.1074/jbc.270.45.27235 PubMed DOI

Kohn A. (1903). Die paraganglien. Arch. Mikrosk. Anat. 52 262–365. 10.1007/BF02985550 DOI

Kuhlbrodt K., Herbarth B., Sock E. I, Hermans-Borgmeyer I., Wegner M. (1998). Sox10, a novel transcriptional modulator in glial cells. J. Neurosci. 18 237–250. 10.1523/JNEUROSCI.18-01-00237.1998 PubMed DOI PMC

Laranjeira C., Sandgren K., Kessaris N., Richardson W., Potocnik A., Vanden Berghe P., et al. (2011). Glial cells in the mouse enteric nervous system can undergo neurogenesis in response to injury. J. Clin. Invest. 121 3412–3424. 10.1172/JCI58200 PubMed DOI PMC

Lenders J. W., Duh Q. Y., Eisenhofer G., Gimenez-Roqueplo A. P., Grebe S. K., Murad M. H., et al. (2014). Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 99 1915–1942. 10.1210/jc.2014-1498 PubMed DOI

Leone D. P., Genoud S., Atanasoski S., Grausenburger R., Berger P., Metzger D., et al. (2003). Tamoxifen-inducible glia-specific Cre mice for somatic mutagenesis in oligodendrocytes and Schwann cells. Mol. Cell. Neurosci. 22 430–440. 10.1016/S1044-7431(03)00029-0 PubMed DOI

Lloyd R. V., Osamura R. Y., Klöppel G., Rosai J. (2017). World Health Organization, International Agency for Research on Cancer, WHO Classification of Tumours of Endocrine Organs, Vol. 10. Geneva: World Health Organization.

Lo L., Tiveron M. C., Anderson D. J. (1998). MASH1 activates expression of the paired homeodomain transcription factor Phox2a, and couples pan-neuronal and subtype-specific components of autonomic neuronal identity. Development 125 609–620. PubMed

Lo L. C., Johnson J. E., Wuenschell C. W., Saito T., Anderson D. J. (1991). Mammalian achaete-scute homolog 1 is transiently expressed by spatially restricted subsets of early neuroepithelial and neural crest cells. Genes Dev. 5 1524–1537. 10.1101/gad.5.9.1524 PubMed DOI

Lumb R., Tata M., Xu X., Joyce A., Marchant C., Harvey N., et al. (2018). Neuropilins guide preganglionic sympathetic axons and chromaffin cell precursors to establish the adrenal medulla. Development 145:dev162552. 10.1242/dev.162552 PubMed DOI PMC

Martucci V. L., Pacak K. (2014). Pheochromocytoma and paraganglioma: diagnosis, genetics, management, and treatment. Curr. Probl. Cancer 38 7–41. 10.1016/j.currproblcancer.2014.01.001 PubMed DOI PMC

Pachnis V., Mankoo B., Costantini F. (1993). Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119 1005–1017. PubMed

Parker T. L., Kesse W. K., Mohamed A. A., Afework M. (1993). The innervation of the mammalian adrenal gland. J. Anat. 183(Pt 2),265–276. PubMed PMC

Portbury A. L., Chandra R., Groelle M., McMillian M. K., Elias A., Herlong J. R., et al. (2003). Catecholamines act via a beta-adrenergic receptor to maintain fetal heart rate and survival. Am. J. Physiol. Heart Circ. Physiol. 284 H2069–H2077. 10.1152/ajpheart.00588.2002 PubMed DOI

Ream M. A., Chandra R., Peavey M., Ray A. M., Roffler-Tarlov S., Kim H. G., et al. (2008). High oxygen prevents fetal lethality due to lack of catecholamines. Am. J. Physiol. Regul. Integr. Comp. Physiol. 295 R942–R953. 10.1152/ajpregu.00860.2007 PubMed DOI PMC

Rios M., Habecker B., Sasaoka T., Eisenhofer G., Tian H., Landis S., et al. (1999). Catecholamine synthesis is mediated by tyrosinase in the absence of tyrosine hydroxylase. J. Neurosci. 19 3519–3526. 10.1523/JNEUROSCI.19-09-03519.1999 PubMed DOI PMC

Saito D., Takase Y., Murai H., Takahashi Y. (2012). The dorsal aorta initiates a molecular cascade that instructs sympatho-adrenal specification. Science 336 1578–1581. 10.1126/science.1222369 PubMed DOI

Schindelin J., Arganda-Carreras I., Frise E., Kaynig V., Longair M., Pietzsch T., et al. (2012). Fiji: an open-source platform for biological-image analysis. Nat. Methods 9 676–682. 10.1038/nmeth.2019 PubMed DOI PMC

Schober A., Parlato R., Huber K., Kinscherf R., Hartleben B., Huber T. B., et al. (2013). Cell loss and autophagy in the extra-adrenal chromaffin organ of Zuckerkandl are regulated by glucocorticoid signalling. J. Neuroendocrinol. 25 34–47. 10.1111/j.1365-2826.2012.02367.x PubMed DOI PMC

Thaler J. P., Koo S. J., Kania A., Lettieri K., Andrews S., Cox C., et al. (2004). A postmitotic role for Isl-class LIM homeodomain proteins in the assignment of visceral spinal motor neuron identity. Neuron 41 337–350. 10.1016/S0896-6273(04)00011-X PubMed DOI

Thomas S. A., Matsumoto A. M., Palmiter R. D. (1995). Noradrenaline is essential for mouse fetal development. Nature 374 643–646. 10.1038/374643a0 PubMed DOI

Uesaka T., Nagashimada M., Enomoto H. (2015). Neuronal differentiation in schwann cell lineage underlies postnatal neurogenesis in the enteric nervous system. J. Neurosci. 35 9879–9888. 10.1523/JNEUROSCI.1239-15.2015 PubMed DOI PMC

West G. B., Shepherd D. M., Hunter R. B., Macgregor A. R. (1953). The function of the organs of Zuckerkandl. Clin. Sci. 12 317–325. PubMed

Yang X., Arber S., William C., Li L., Tanabe Y., Jessell T. M., et al. (2001). Patterning of muscle acetylcholine receptor gene expression in the absence of motor innervation. Neuron 30 399–410. 10.1016/S0896-6273(01)00287-2 PubMed DOI

Zhou Q. Y., Quaife C. J., Palmiter R. D. (1995). Targeted disruption of the tyrosine hydroxylase gene reveals that catecholamines are required for mouse fetal development. Nature 374 640–643. 10.1038/374640a0 PubMed DOI

Zuckerkandl E. (1901). About sympathetic paraganglions in the retroperitoneal space of man. (Über Nebenorgane des sympathacus im retroperitonealraum des menschen). Verh. Anat. Ges. 15 95–107.

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