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Mouse Models for Studying Hippocampal Adult Neural Stem Cell Biology

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Mouse Genetics

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2224))

Abstract

The mammalian hippocampus shows a remarkable capacity for continued neurogenesis throughout life. Newborn neurons, generated by the radial neural stem cells (NSCs), are important for learning and memory as well as mood control. During aging, the number and responses of NSCs to neurogenic stimuli diminish, leading to decreased neurogenesis and age-associated cognitive decline and psychiatric disorders. Thus, adult hippocampal neurogenesis has been the subject of intense investigation, generating both excitement and controversy. Identifying the core molecular machinery responsible for NSC preservation is of fundamental importance if we are to use neurogenesis to halt or reverse hippocampal age-related pathology. Here, we briefly overview the most frequently used mouse models to study hippocampal neurogenesis and then focus on a unique mouse model that allows NSC-specific studies based on their unique expression of lunatic fringe (Lfng). The Lfng-eGFP and Lfng(BAC)-CreERT2;RCL-tdT transgenic mice provide us with an excellent tool to resolve long-standing questions regarding the properties of NSCs, such as their specific molecular composition, potency, and plasticity, in isolation from any other cell in the hippocampal neurogenic niche.

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References

  1. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA et al (1998) Neurogenesis in the adult human hippocampus. Nat Med 4(11):1313–1317

    Article  CAS  PubMed  Google Scholar 

  2. Boldrini M, Fulmore CA, Tartt AN, Simeon LR, Pavlova I, Poposka V et al (2018) Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell 22(4):589–99.e5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Moreno-Jiménez EP, Flor-García M, Terreros-Roncal J, Rábano A, Cafini F, Pallas-Bazarra N et al (2019) Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat Med 25(4):554–560

    Article  PubMed  CAS  Google Scholar 

  4. Manganas LN, Zhang X, Li Y, Hazel RD, Smith SD, Wagshul ME et al (2007) Magnetic resonance spectroscopy identifies neural progenitor cells in the live human brain. Science (New York, NY) 318(5852):980–985

    Article  CAS  Google Scholar 

  5. Djuric PM, Benveniste H, Wagshul ME, Henn F, Enikolopov G, Maletic-Savatic M (2008) Response to comments on “magnetic resonance spectroscopy identifies neural progenitor cells in the live human brain”. Science 321(5889):640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Knoth R, Singec I, Ditter M, Pantazis G, Capetian P, Meyer RP et al (2010) Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years. PLoS One 5(1):e8809

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Pereira AC, Huddleston DE, Brickman AM, Sosunov AA, Hen R, McKhann GM et al (2007) An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci U S A 104(13):5638–5643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Quiñones-Hinojosa A, Sanai N, Soriano-Navarro M, Gonzalez-Perez O, Mirzadeh Z, Gil-Perotin S et al (2006) Cellular composition and cytoarchitecture of the adult human subventricular zone: a niche of neural stem cells. J Comp Neurol 494(3):415–434

    Article  PubMed  Google Scholar 

  9. Sierra A, Encinas JM, Maletic-Savatic M (2011) Adult human neurogenesis: from microscopy to magnetic resonance imaging. Front Neurosci 5:47

    Article  PubMed  PubMed Central  Google Scholar 

  10. Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB et al (2013) Dynamics of hippocampal neurogenesis in adult humans. Cell 153(6):1219–1227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. David DJ, Samuels BA, Rainer Q, Wang JW, Marsteller D, Mendez I et al (2009) Neurogenesis- dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron 62(4):479–493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Anacker C, Hen R (2017) Adult hippocampal neurogenesis and cognitive flexibility - linking memory and mood. Nat Rev Neurosci 18(6):335–346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dard RF, Dahan L, Rampon C (2019) Targeting hippocampal adult neurogenesis using transcription factors to reduce Alzheimer's disease-associated memory impairments. Hippocampus 29(7):579–586

    Article  PubMed  Google Scholar 

  14. Llorens-Martin M (2018) Exercising new neurons to vanquish Alzheimer Disease. Brain Plast 4(1):111–126

    Article  PubMed  PubMed Central  Google Scholar 

  15. Tobin MK, Musaraca K, Disouky A, Shetti A, Bheri A, Honer WG et al (2019) Human hippocampal neurogenesis persists in aged adults and Alzheimer's disease patients. Cell Stem Cell 24(6):974–82 e3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lucassen PJ, Stumpel MW, Wang Q, Aronica E (2010) Decreased numbers of progenitor cells but no response to antidepressant drugs in the hippocampus of elderly depressed patients. Neuropharmacology 58(6):940–949

    Article  CAS  PubMed  Google Scholar 

  17. Gandy K, Kim S, Sharp C, Dindo L, Maletic-Savatic M, Calarge C (2017) Pattern separation: a potential marker of impaired hippocampal adult neurogenesis in major depressive disorder. Front Neurosci 11:571

    Article  PubMed  PubMed Central  Google Scholar 

  18. Manganas LN, Maletic-Savatic M (2005) Stem cell therapy for central nervous system demyelinating disease. Curr Neurol Neurosci Rep 5(3):225–231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Paizanis E, Hamon M, Lanfumey L (2007) Hippocampal neurogenesis, depressive disorders, and antidepressant therapy. Neural Plast 2007:73754

    Article  PubMed  PubMed Central  Google Scholar 

  20. Martin-Suarez S, Valero J, Muro-Garcia T, Encinas JM (2019) Phenotypical and functional heterogeneity of neural stem cells in the aged hippocampus. Aging Cell 18:e12958

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Dulken BW, Leeman DS, Boutet SC, Hebestreit K, Brunet A (2017) Single-cell transcriptomic analysis defines heterogeneity and transcriptional dynamics in the adult neural stem cell lineage. Cell Rep 18(3):777–790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gebara E, Bonaguidi MA, Beckervordersandforth R, Sultan S, Udry F, Gijs PJ et al (2016) Heterogeneity of radial glia-like cells in the adult hippocampus. Stem Cells 34:997–1010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tosun M, Semerci F, Maletic-Savatic M (2019) Heterogeneity of stem cells in the hippocampus. Adv Exp Med Biol 1169:31–53

    Article  CAS  PubMed  Google Scholar 

  24. Semerci F, Maletic-Savatic M (2016) Transgenic mouse models for studying adult neurogenesis. Front Biol (Beijing) 11(3):151–167

    Article  CAS  Google Scholar 

  25. Lendahl U, Zimmerman LB, McKay RDG (1990) CNS stem cells express a new class of intermediate filament protein. Cell 60(4):585–595

    Article  CAS  PubMed  Google Scholar 

  26. Day K, Shefer G, Richardson JB, Enikolopov G, Yablonka-Reuveni Z (2007) Nestin-GFP reporter expression defines the quiescent state of skeletal muscle satellite cells. Dev Biol 304(1):246–259

    Article  CAS  PubMed  Google Scholar 

  27. Wiese C, Rolletschek A, Kania G, Blyszczuk P, Tarasov K, Tarasova Y et al (2004) Nestin expression–a property of multi-lineage progenitor cells? Cell Mol Life Sci 61(19–20):2510–2522

    Article  CAS  PubMed  Google Scholar 

  28. Lobo MV, Arenas MI, Alonso FJ, Gomez G, Bazan E, Paino CL et al (2004) Nestin, a neuroectodermal stem cell marker molecule, is expressed in Leydig cells of the human testis and in some specific cell types from human testicular tumours. Cell Tissue Res 316(3):369–376

    Article  CAS  PubMed  Google Scholar 

  29. Mayer EJ, Hughes EH, Carter DA, Dick AD (2003) Nestin positive cells in adult human retina and in epiretinal membranes. Br J Ophthalmol 87(9):1154–1158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Li L, Mignone J, Yang M, Matic M, Penman S, Enikolopov G et al (2003) Nestin expression in hair follicle sheath progenitor cells. Proc Natl Acad Sci U S A 100(17):9958–9961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Mignone JL, Roig-Lopez JL, Fedtsova N, Schones DE, Manganas LN, Maletic-Savatic M et al (2007) Neural potential of a stem cell population in the hair follicle. Cell Cycle 6(17):2161–2170

    Article  CAS  PubMed  Google Scholar 

  32. Neradil J, Veselska R (2015) Nestin as a marker of cancer stem cells. Cancer Sci 106(7):803–811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yamaguchi M, Saito H, Suzuki M, Mori K (2000) Visualization of neurogenesis in the central nervous system using nestin promoter-GFP transgenic mice. Neuroreport 11(9):1991–1996

    Article  CAS  PubMed  Google Scholar 

  34. Mignone JL, Kukekov V, Chiang AS, Steindler D, Enikolopov G (2004) Neural stem and progenitor cells in nestin-GFP transgenic mice. J Comp Neurol 469(3):311–324

    Article  CAS  PubMed  Google Scholar 

  35. Encinas JM, Vaahtokari A, Enikolopov G (2006) Fluoxetine targets early progenitor cells in the adult brain. Proc Natl Acad Sci U S A 103(21):8233–8238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Dupret D, Revest J-M, Koehl M, Ichas F, De Giorgi F, Costet P et al (2008) Spatial relational memory requires hippocampal adult neurogenesis. PLoS One 3(4):e1959

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Balordi F, Fishell G (2007) Mosaic removal of hedgehog signaling in the adult SVZ reveals that the residual wild-type stem cells have a limited capacity for self-renewal. J Neurosci 27(52):14248–14259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Williams SM, Sullivan RK, Scott HL, Finkelstein DI, Colditz PB, Lingwood BE et al (2005) Glial glutamate transporter expression patterns in brains from multiple mammalian species. Glia 49(4):520–541

    Article  PubMed  Google Scholar 

  39. DeCarolis NA, Mechanic M, Petrik D, Carlton A, Ables JL, Malhotra S et al (2013) In vivo contribution of nestin- and GLAST-lineage cells to adult hippocampal neurogenesis. Hippocampus 23(8):708–719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bertrand N, Castro DS, Guillemot F (2002) Proneural genes and the specification of neural cell types. Nat Rev Neurosci 3(7):517–530

    Article  CAS  PubMed  Google Scholar 

  41. Kim EJ, Leung CT, Reed RR, Johnson JE (2007) In vivo analysis of Ascl1 defined progenitors reveals distinct developmental dynamics during adult neurogenesis and gliogenesis. J Neurosci 27(47):12764–12774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kim EJ, Ables JL, Dickel LK, Eisch AJ, Johnson JE (2011) Ascl1 (Mash1) defines cells with long-term neurogenic potential in subgranular and subventricular zones in adult mouse brain. PloS One 6(3):e18472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yang SM, Alvarez DD, Schinder AF (2015) Reliable genetic labeling of adult-born dentate granule cells using Ascl1 CreERT2 and Glast CreERT2 murine lines. J Neurosci 35(46):15379–15390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hynes M, Stone DM, Dowd M, Pitts-Meek S, Goddard A, Gurney A et al (1997) Control of cell pattern in the neural tube by the zinc finger transcription factor and oncogene Gli-1. Neuron 19(1):15–26

    Article  CAS  PubMed  Google Scholar 

  45. Encinas JM, Michurina TV, Peunova N, Park JH, Tordo J, Peterson DA et al (2011) Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell 8(5):566–579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Alunni A, Krecsmarik M, Bosco A, Galant S, Pan L, Moens CB et al (2013) Notch3 signaling gates cell cycle entry and limits neural stem cell amplification in the adult pallium. Development 140(16):3335–3347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Breunig JJ, Silbereis J, Vaccarino FM, Sestan N, Rakic P (2007) Notch regulates cell fate and dendrite morphology of newborn neurons in the postnatal dentate gyrus. Proc Natl Acad Sci U S A 104(51):20558–20563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Giachino C, Basak O, Lugert S, Knuckles P, Obernier K, Fiorelli R et al (2014) Molecular diversity subdivides the adult forebrain neural stem cell population. Stem Cells 32(1):70–84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Basak O, Taylor V (2007) Identification of self-replicating multipotent progenitors in the embryonic nervous system by high Notch activity and Hes5 expression. Eur J Neurosci 25(4):1006–1022

    Article  PubMed  Google Scholar 

  50. Lugert S, Basak O, Knuckles P, Haussler U, Fabel K, Gotz M et al (2010) Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging. Cell Stem Cell 6(5):445–456

    Article  CAS  PubMed  Google Scholar 

  51. Lugert S, Vogt M, Tchorz JS, Muller M, Giachino C, Taylor V (2012) Homeostatic neurogenesis in the adult hippocampus does not involve amplification of Ascl1(high) intermediate progenitors. Nat Commun 3:670

    Article  PubMed  CAS  Google Scholar 

  52. Knobloch M, Braun SM, Zurkirchen L, von Schoultz C, Zamboni N, Arauzo-Bravo MJ et al (2013) Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis. Nature 493(7431):226–230

    Article  CAS  PubMed  Google Scholar 

  53. Knobloch M, von Schoultz C, Zurkirchen L, Braun SMG, Vidmar M, Jessberger S (2014) SPOT14-positive neural stem/progenitor cells in the hippocampus respond dynamically to neurogenic regulators. Stem Cell Rep 3(5):735–742

    Article  CAS  Google Scholar 

  54. Ables JL, DeCarolis NA, Johnson MA, Rivera PD, Gao Z, Cooper DC et al (2010) Notch1 Is required for maintenance of the reservoir of adult hippocampal stem cells. J Neurosci 30(31):10484–10492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Semerci F, Choi WT-S, Bajic A, Thakkar A, Encinas JM, Depreux F et al (2017) Lunatic fringe-mediated Notch signaling regulates adult hippocampal neural stem cell maintenance. elife 6:e24660

    Article  PubMed  PubMed Central  Google Scholar 

  56. Gong S, Zheng C, Doughty ML, Losos K, Didkovsky N, Schambra UB et al (2003) A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature 425(6961):917–925

    Article  CAS  PubMed  Google Scholar 

  57. Madisen L, Zwingman TA, Sunkin SM, Oh SW, Zariwala HA, Gu H et al (2010) A robust and high- throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci 13(1):133–140

    Article  CAS  PubMed  Google Scholar 

  58. Encinas JM, Enikolopov G (2008) Identifying and quantitating neural stem and progenitor cells in the adult brain. Methods Cell Biol 85:243–272 https://doi.org/10.1038/s41467-020-18046-y

  59. Dranovsky A, Picchini AM, Moadel T, Sisti AC, Yamada A, Kimura S et al (2011) Experience dictates stem cell fate in the adult hippocampus. Neuron 70(5):908–923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Andersen J, Urban N, Achimastou A, Ito A, Simic M, Ullom K et al (2014) A transcriptional mechanism integrating inputs from extracellular signals to activate hippocampal stem cells. Neuron 83(5):1085–1097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Matsuda S, Kuwako K, Okano HJ, Tsutsumi S, Aburatani H, Saga Y et al (2012) Sox21 promotes hippocampal adult neurogenesis via the transcriptional repression of the Hes5 gene. J Neurosci 32(36):12543–12557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Venere M, Han YG, Bell R, Song JS, Alvarez-Buylla A, Blelloch R (2012) Sox1 marks an activated neural stem/progenitor cell in the hippocampus. Development 139(21):3938–3949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Sierra A, Encinas JM, Deudero JJ, Chancey JH, Enikolopov G, Overstreet-Wadiche LS et al (2010) Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7(4):483–495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Diaz-Aparicio I, Paris I, Sierra-Torre V, Plaza-Zabala A, Rodríguez-Iglesias N, Márquez-Ropero M et al (2019) Microglia actively remodels adult hippocampal neurogenesis through the phagocytosis secretome. bioRxiv:583849

    Google Scholar 

  65. Lucassen PJ, van Dam A-M, Kandel P, Bielefeld P, Korosi A, Fitzsimons CP et al (2019) The orphan nuclear receptor TLX: an emerging master regulator of crosstalk between microglia and neural precursor cells. Neuronal Signal 3(2):NS20180208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We would like to thank the members of Maletic-Savatic lab for helpful discussions on this topic. This work was supported by the NIH R01GM120033-01 to M.M.S.

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Correspondence to Mirjana Maletic-Savatic .

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Semerci, F., Parkitny, L., Maletic-Savatic, M. (2021). Mouse Models for Studying Hippocampal Adult Neural Stem Cell Biology. In: Singh, S.R., Hoffman, R.M., Singh, A. (eds) Mouse Genetics . Methods in Molecular Biology, vol 2224. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1008-4_4

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  • DOI: https://doi.org/10.1007/978-1-0716-1008-4_4

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