The 1st-generation neural precursors in the crustacean brain are functionally analogous to neural stem cells in mammals. Their slow cycling, migration of their progeny, and differentiation of their descendants into neurons over several weeks are features of the neural precursor lineage in crayfish that also characterize adult neurogenesis in mammals. However, the 1st-generation precursors in crayfish do not self-renew, contrasting with conventional wisdom that proposes the long-term self-renewal of adult neural stem cells. Nevertheless, the crayfish neurogenic niche, which contains a total of 200-300 cells, is never exhausted and neurons continue to be produced in the brain throughout the animal's life. The pool of neural precursors in the niche therefore cannot be a closed system, and must be replenished from an extrinsic source. Our in vitro and in vivo data show that cells originating in the innate immune system (but not other cell types) are attracted to and incorporated into the neurogenic niche, and that they express a niche-specific marker, glutamine synthetase. Further, labeled hemocytes that undergo adoptive transfer to recipient crayfish generate cells in neuronal clusters in the olfactory pathway of the adult brain. These hemocyte descendants express appropriate neurotransmitters and project to target areas typical of neurons in these regions. These studies indicate that under natural conditions, the immune system provides neural precursors supporting adult neurogenesis in the crayfish brain, challenging the canonical view that ectodermal tissues generating the embryonic nervous system are the sole source of neurons in the adult brain. However, these are not the first studies that directly implicate the immune system as a source of neural precursor cells. Several types of data in mammals, including adoptive transfers of bone marrow or stem cells as well as the presence of fetal microchimerism, suggest that there must be a population of cells that are able to access the brain and generate new neurons in these species.

Keywords:
Adult neural stem cells, Immune system, Self-renewal, Hemocytes, Bone marrow, Blood-brain barrier
1.
Bear MF, Connors BW, Paradiso MA (2016): Neuroscience: Exploring the Brain, ed 4. New York, Wolters Kluwer, p 873.
2.
Beltz BS, Cockey EL, Li J, Platto JF, Ramos KA, Benton JL (2015): Adult neural stem cells: long-term self-renewal, replenishment by the immune system, or both? Bioessays 37:495-501.
3.
Beltz BS, Zhang Y, Benton JL, Sandeman DC (2011): Adult neurogenesis in the decapod crustacean brain: a hematopoietic connection? Eur J Neurosci 34:870-883.
4.
Benton JL, Chaves da Silva PG, Sandeman DC, Beltz BS (2013): First-generation neuronal precursors in the crayfish brain are not self-renewing. Int J Dev Neurosci 31:657-666.
5.
Benton JL, Kery R, Li J, Noonin C, Soderhall I, Beltz BS (2014): Cells from the immune system generate adult-born neurons in crayfish. Dev Cell 30:322-333.
6.
Benton JL, Zhang Y, Kirkhart CR, Sandeman DC, Beltz BS (2011): Primary neuronal precursors in adult crayfish brain: replenishment from a non-neuronal source. BMC Neurosci 12:53.
7.
Bonaguidi MA, Wheeler MA, Shapiro JS, Stadel RP, Sun GJ, Ming GL, Song H (2011): In vivo clonal analysis reveals self-renewing and multipotent adult neural stem cell characteristics. Cell 145:1142-1155.
8.
Brand AH, Livesey FJ (2011): Neural stem cell biology in vertebrates and invertebrates: more alike than different? Neuron 70:719-729.
9.
Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A, Toth M, Korecka A, Bakocevic N, Ng LG, Kundu P, Gulyas B, Halldin C, Hultenby K, Nilsson H, Hebert H, Volpe BT, Diamond B, Pettersson S (2014): The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med 6:263ra158.
10.
Brazelton TR, Rossi FM, Keshet GI, Blau HM (2000): From marrow to brain: expression of neuronal phenotypes in adult mice. Science 290:1775-1779.
11.
Calzolari F, Michel J, Baumgart EV, Theis F, Gotz M, Ninkovic J (2015): Fast clonal expansion and limited neural stem cell self-renewal in the adult subependymal zone. Nat Neurosci 18:490-492.
12.
Chan WF, Gurnot C, Montine TJ, Sonnen JA, Guthrie KA, Nelson JL (2012): Male microchimerism in the human female brain. PloS One 7:e45592.
13.
Chaves da Silva PG, Benton JL, Beltz BS, Allodi S (2012): Adult neurogenesis: ultrastructure of a neurogenic niche and neurovascular relationships. PloS One 7:e39267.
14.
Cockey E, Li J, Benton JL, Beltz BS (2015): Cytokine regulation of adult neurogenesis: The immune system provides neuronal precursors for adult neurogenesis. Soc for Neurosci Abstracts, p 289.215.
15.
Cogle CR, Yachnis AT, Laywell ED, Zander DS, Wingard JR, Steindler DA, Scott EW (2004): Bone marrow transdifferentiation in brain after transplantation: a retrospective study. Lancet 363:1432-1437.
16.
Doe CQ (2008): Neural stem cells: balancing self-renewal with differentiation. Development 135:1575-1587.
17.
Eisch AJ, Cameron HA, Encinas JM, Meltzer LA, Ming GL, Overstreet-Wadiche LS (2008): Adult neurogenesis, mental health, and mental illness: hope or hype? J Neurosci 28:11785-11791.
18.
Encinas JM, Michurina TV, Peunova N, Park JH, Tordo J, Peterson DA, Fishell G, Koulakov A, Enikolopov G (2011): Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell 8:566-579.
19.
Fuentealba LC, Rompani SB, Parraguez JI, Obernier K, Romero R, Cepko CL, Alvarez-Buylla A (2015): Embryonic origin of postnatal neural stem cells. Cell 161:1644-1655.
20.
Gomez-Gonzalez B, Hurtado-Alvarado G, Esqueda-Leon E, Santana-Miranda R, Rojas-Zamorano JA, Velazquez-Moctezuma J (2013): REM sleep loss and recovery regulates blood-brain barrier function. Curr Neurovasc Res 10:197-207.
21.
Gonzalez-Perez O, Gutierrez-Fernandez F, Lopez-Virgen V, Collas-Aguilar J, Quinones-Hinojosa A, Garcia-Verdugo JM (2012): Immunological regulation of neurogenic niches in the adult brain. Neuroscience 226:270-281.
22.
Gonzalez-Perez O, Quinones-Hinojosa A, Garcia-Verdugo JM (2010): Immunological control of adult neural stem cells. J Stem Cells 5:23-31.
23.
Greenwood J, Heasman SJ, Alvarez JI, Prat A, Lyck R, Engelhardt B (2011): Review: leucocyte-endothelial cell crosstalk at the blood-brain barrier: a prerequisite for successful immune cell entry to the brain. Neuropathol Appl Neurobiol 37:24-39.
24.
Hartenstein V, Stollewerk A (2015): The evolution of early neurogenesis. Dev Cell 32:390-407.
25.
He J, Hsuchou H, He Y, Kastin AJ, Wang Y, Pan W (2014): Sleep restriction impairs blood-brain barrier function. J Neurosci 34:14697-14706.
26.
Jearaphunt M, Noonin C, Jiravanichpaisal P, Nakamura S, Tassanakajon A, Soderhall I, Soderhall K (2014): Caspase-1-like regulation of the proPO-system and role of ppA and caspase-1-like cleaved peptides from proPO in innate immunity. PLoS Pathog 10:e1004059.
27.
Kan I, Barhum Y, Melamed E, Offen D (2011): Mesenchymal stem cells stimulate endogenous neurogenesis in the subventricular zone of adult mice. Stem Cell Rev 7:404-412.
28.
Keaney J, Campbell M (2015): The dynamic blood-brain barrier. FEBS J 282:4067-4079.
29.
Kee Y, Hwang BJ, Sternberg PW, Bronner-Fraser M (2007): Evolutionary conservation of cell migration genes: from nematode neurons to vertebrate neural crest. Genes Dev 21:391-396.
30.
Kiel MJ, He S, Ashkenazi R, Gentry SN, Teta M, Kushner JA, Jackson TL, Morrison SJ (2007): Haematopoietic stem cells do not asymmetrically segregate chromosomes or retain BrdU. Nature 449:238-242.
31.
Kim Y, Sandeman DC, Benton JL, Beltz BS (2014): Birth, survival and differentiation of neurons in an adult crustacean brain. Dev Neurobiol 74:602-615.
32.
Lee JH, Mitchell RR, McNicol JD, Shapovalova Z, Laronde S, Tanasijevic B, Milsom C, Casado F, Fiebig-Comyn A, Collins TJ, Singh KK, Bhatia M (2015): Single transcription factor conversion of human blood fate to NPCs with CNS and PNS developmental capacity. Cell Rep 11:1367-1376.
33.
Lee PH, Park HJ (2009): Bone marrow-derived mesenchymal stem cell therapy as a candidate disease-modifying strategy in Parkinson's disease and multiple system atrophy. J Clin Neurol 5:1-10.
34.
Lemaire V, Koehl M, Le Moal M, Abrous DN (2000): Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus. Proc Natl Acad Sci USA 97:11032-11037.
35.
Li Y, Chen J, Chen XG, Wang L, Gautam SC, Xu YX, Katakowski M, Zhang LJ, Lu M, Janakiraman N, Chopp M (2002): Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery. Neurology 59:514-523.
36.
Lin R, Iacovitti L (2015): Classic and novel stem cell niches in brain homeostasis and repair. Brain Res 1628:327-342.
37.
Lin X, Novotny M, Söderhäll K, Söderhäll I (2010): Ancient cytokines, the role of astakines as hematopoietic growth factors. J Biol Chem 285:28577-28586.
38.
Lin X, Söderhäll I (2011): Crustacean hematopoiesis and the astakine cytokines. Blood 117:6417-6424.
39.
Lin X, Söderhäll K, Söderhäll I (2011): Invertebrate hematopoiesis: an astakine-dependent novel hematopoietic factor. J Immunol 186:2073-2079.
40.
Liu L, Eckert MA, Riazifar H, Kang DK, Agalliu D, Zhao W (2013): From blood to the brain: can systemically transplanted mesenchymal stem cells cross the blood-brain barrier? Stem Cells Int 2013:435093.
41.
Luo Y, Coskun V, Liang A, Yu J, Cheng L, Ge W, Shi Z, Zhang K, Li C, Cui Y, Lin H, Luo D, Wang J, Lin C, Dai Z, Zhu H, Zhang J, Liu J, Liu H, deVellis J, Horvath S, Sun YE, Li S (2015): Single-cell transcriptome analyses reveal signals to activate dormant neural stem cells. Cell 161:1175-1186.
42.
Maltman DJ, Hardy SA, Przyborski SA (2011): Role of mesenchymal stem cells in neurogenesis and nervous system repair. Neurochem Int 59:347-356.
43.
Mezey E (2011): The therapeutic potential of bone marrow-derived stromal cells. J Cell Biochem 112:2683-2687.
44.
Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR (2000): Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 290:1779-1782.
45.
Mezey E, Key S, Vogelsang G, Szalayova I, Lange GD, Crain B (2003): Transplanted bone marrow generates new neurons in human brains. Proc Natl Acad Sci USA 100:1364-1369.
46.
Ming GL, Song H (2011): Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70:687-702.
47.
Munoz-Elias G, Marcus AJ, Coyne TM, Woodbury D, Black IB (2004): Adult bone marrow stromal cells in the embryonic brain: engraftment, migration, differentiation, and long-term survival. J Neurosci 24:4585-4595.
48.
Ng KL, Li JD, Cheng MY, Leslie FM, Lee AG, Zhou QY (2005): Dependence of olfactory bulb neurogenesis on prokineticin 2 signaling. Science 308:1923-1927.
49.
Noonin C, Lin X, Jiravanichpaisal P, Soderhall K, Soderhall I (2012): Invertebrate hematopoiesis: an anterior proliferation center as a link between the hematopoietic tissue and the brain. Stem Cells Dev 21:3173-3186.
50.
Otopalik AG, Shin J, Beltz BS, Sandeman DC, Kolodny NH (2012): Differential uptake of MRI contrast agents indicates charge-selective blood-brain interface in the crayfish. Cell Tissue Res 349:493-503.
51.
Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, Giustetto M, Ferreira TA, Guiducci E, Dumas L, Ragozzino D, Gross CT (2011): Synaptic pruning by microglia is necessary for normal brain development. Science 333:1456-1458.
52.
Perry VH, Andersson PB, Gordon S (1993): Macrophages and inflammation in the central nervous system. Trends Neurosci 16:268-273.
53.
Perry VH, Nicoll JA, Holmes C (2010): Microglia in neurodegenerative disease. Nat Rev Neurol 6:193-201.
54.
Platto JF (2015): Targets and Transmitters: The Fate of Brain Cells Derived from Adoptive Transfers of Hemocytes; honors thesis, Wellesley College, Wellesley, p 31.
55.
Sagar D, Foss C, El Baz R, Pomper MG, Khan ZK, Jain P (2012): Mechanisms of dendritic cell trafficking across the blood-brain barrier. J Neuroimmune Pharmacol 7:74-94.
56.
Sanchez-Ramos J, Song S, Cardozo-Pelaez F, Hazzi C, Stedeford T, Willing A, Freeman TB, Saporta S, Janssen W, Patel N, Cooper DR, Sanberg PR (2000): Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol 164:247-256.
57.
Sandeman D, Sandeman R, Derby C, Schmidt M (1992): Morphology of the brain of crayfish, crabs, and spiny lobsters: a common nomenclature for homologous structures. Biol Bull 183:340-346.
58.
Sandeman DC, Benton JL, Beltz BS (2009): An identified serotonergic neuron regulates adult neurogenesis in the crustacean brain. Dev Neurobiol 69:530-545.
59.
Schmidt M (2016): Malacostraca; in Schmidt-Rhaesa A, Harzsch S, Purschke G (eds): Structure and Evolution of Invertebrate Nervous Systems. Oxford University Press, Oxford, UK.
60.
Schmidt M, Harzch S (1999): Comparative analysis of neurogenesis in the central olfactory pathway of adult decapod crustaceans by in vivo BrdU labeling. Biol Bull 196:127-136.
61.
Shapiro E, Krivit W, Lockman L, Jambaque I, Peters C, Cowan M, Harris R, Blanche S, Bordigoni P, Loes D, Ziegler R, Crittenden M, Ris D, Berg B, Cox C, Moser H, Fischer A, Aubourg P (2000): Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy. Lancet 356:713-718.
62.
Shors TJ (2004): Memory traces of trace memories: neurogenesis, synaptogenesis and awareness. Trends Neurosci 27:250-256.
63.
Söderhäll I, Kim YA, Jiravanichpaisal P, Lee SY, Soderhall K (2005): An ancient role for a prokineticin domain in invertebrate hematopoiesis. J Immunol 174:6153-6160.
64.
Southall TD, Brand AH (2009): Neural stem cell transcriptional networks highlight genes essential for nervous system development. EMBO J 28:3799-3807.
65.
Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, Bostrom E, Westerlund I, Vial C, Buchholz BA, Possnert G, Mash DC, Druid H, Frisen J (2013): Dynamics of hippocampal neurogenesis in adult humans. Cell 153:1219-1227.
66.
Stergiopoulos A, Elkouris M, Politis PK (2015): Prospero-related homeobox 1 (Prox1) at the crossroads of diverse pathways during adult neural fate specification. Front Cell Neurosci 8:454.
67.
Sullivan JM, Beltz BS (2005): Newborn cells in the adult crayfish brain differentiate into distinct neuronal types. J Neurobiol 65:157-170.
68.
Sullivan JM, Benton JL, Sandeman DC, Beltz BS (2007): Adult neurogenesis: a common strategy across diverse species. J Comp Neurol 500:574-584.
69.
Tan XW, Liao H, Sun L, Okabe M, Xiao ZC, Dawe GS (2005): Fetal microchimerism in the maternal mouse brain: a novel population of fetal progenitor or stem cells able to cross the blood-brain barrier? Stem Cells 23:1443-1452.
70.
Tavazoie M, Van der Veken L, Silva-Vargas V, Louissaint M, Colonna L, Zaidi B, Garcia-Verdugo JM, Doetsch F (2008): A specialized vascular niche for adult neural stem cells. Cell Stem Cell 3:279-288.
71.
Zeng XX, Tan KH, Yeo A, Sasajala P, Tan X, Xiao ZC, Dawe G, Udolph G (2010): Pregnancy-associated progenitor cells differentiate and mature into neurons in the maternal brain. Stem Cells Dev 19:1819-1830.
72.
Zhang Y, Allodi S, Sandeman DC, Beltz BS (2009): Adult neurogenesis in the crayfish brain: proliferation, migration, and possible origin of precursor cells. Dev Neurobiol 69:415-436.
73.
Zhang Y, Benton JL, Beltz BS (2011): 5-HT receptors mediate lineage-dependent effects of serotonin on adult neurogenesis in Procambarus clarkii. Neural Dev 6:2.
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2016
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