The Cerebellum

, Volume 17, Issue 1, pp 42–48 | Cite as

The Molecular Pathway Regulating Bergmann Glia and Folia Generation in the Cerebellum

  • Alan W. Leung
  • James Y. H. Li


Evolution of complex behaviors in higher vertebrates and primates require the development of sophisticated neuronal circuitry and the expansion of brain surface area to accommodate the vast number of neuronal and glial populations. To achieve these goals, the neocortex in primates and the cerebellum in amniotes have developed specialized types of basal progenitors to aid the folding of their cortices. In the cerebellum, Bergmann glia constitute such a basal progenitor population, having a distinctive morphology and playing a critical role in cerebellar corticogenesis. Here, we review recent studies on the induction of Bergmann glia and their crucial role in mediating folding of the cerebellar cortex. These studies uncover a key function of FGF-ERK-ETV signaling cascade in the transformation of Bergmann glia from radial glia in the ventricular zone. Remarkably, in the neocortex, the same signaling axis operates to facilitate the transformation of ventricular radial glia into basal radial glia, a Bergmann glia-like basal progenitor population, which have been implicated in the establishment of neocortical gyri. These new findings draw a striking similarity in the function and ontogeny of the two basal progenitor populations born in distinct brain compartments.


Cerebellum Bergmann glia Outer radial glia Foliation Extracellular signal-regulated kinases Human Mouse 



We thank Dr. John Wizeman for the critical proofreading of our manuscript.

Funding Information

This work was supported by a grant from the National Institutes of Health (R01MH094914) to J. Li.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Cui W, Allen ND, Skynner M, Gusterson B, Clark AJ. Inducible ablation of astrocytes shows that these cells are required for neuronal survival in the adult brain. Glia. 2001;34(4):272–82. Scholar
  2. 2.
    Reeber SL, Arancillo M, Sillitoe RV. Bergmann glia are patterned into topographic molecular zones in the developing and adult mouse cerebellum. Cerebellum. 2014.Google Scholar
  3. 3.
    Buffo A, Rossi F. Origin, lineage and function of cerebellar glia. Prog Neurobiol. 2013;109:42–63. Scholar
  4. 4.
    Yuasa S. Bergmann glial development in the mouse cerebellum as revealed by tenascin expression. Anat Embryol (Berl). 1996;194(3):223–34.CrossRefGoogle Scholar
  5. 5.
    Yamada K, Watanabe M. Cytodifferentiation of Bergmann glia and its relationship with Purkinje cells. Anat Sci Int. 2002;77(2):94–108. Scholar
  6. 6.
    de Blas AL. Monoclonal antibodies to specific astroglial and neuronal antigens reveal the cytoarchitecture of the Bergmann glia fibers in the cerebellum. J Neurosci. 1984;4(1):265–73.PubMedGoogle Scholar
  7. 7.
    Bellamy TC. Interactions between Purkinje neurones and Bergmann glia. Cerebellum. 2006;5(2):116–26. Scholar
  8. 8.
    Iino M, Goto K, Kakegawa W, Okado H, Sudo M, Ishiuchi S, et al. Glia-synapse interaction through Ca2+-permeable AMPA receptors in Bergmann glia. Science. 2001;292(5518):926–9. Scholar
  9. 9.
    Parmigiani E, Leto K, Rolando C, Figueres-Onate M, Lopez-Mascaraque L, Buffo A, et al. Heterogeneity and bipotency of astroglial-like cerebellar progenitors along the interneuron and glial lineages. J Neurosci. 2015;35(19):7388–402. Scholar
  10. 10.
    Shiga T, Ichikawa M, Hirata Y. Spatial and temporal pattern of postnatal proliferation of Bergmann glial cells in rat cerebellum: an autoradiographic study. Anat Embryol (Berl). 1983;167(2):203–11. Scholar
  11. 11.
    Das GD, Lammert GL, McAllister JP. Contact guidance and migratory cells in the developing cerebellum. Brain Res. 1974;69(1):13–29. Scholar
  12. 12.
    Alcock J, Lowe J, England T, Bath P, Sottile V. Expression of Sox1, Sox2 and Sox9 is maintained in adult human cerebellar cortex. Neurosci Lett. 2009;450(2):114–6. Scholar
  13. 13.
    Koirala S, Corfas G. Identification of novel glial genes by single-cell transcriptional profiling of Bergmann glial cells from mouse cerebellum. PLoS One. 2010;5(2):e9198. Scholar
  14. 14.
    Sottile V, Li M, Scotting PJ. Stem cell marker expression in the Bergmann glia population of the adult mouse brain. Brain Res. 2006;1099(1):8–17. Scholar
  15. 15.
    Hampson DR, Blatt GJ. Autism spectrum disorders and neuropathology of the cerebellum. Front Neurosci. 2015;9:420. Scholar
  16. 16.
    D'Mello AM, Stoodley CJ. Cerebro-cerebellar circuits in autism spectrum disorder. Front Neurosci. 2015;9:408. Scholar
  17. 17.
    Mosconi MW, Wang Z, Schmitt LM, Tsai P, Sweeney JA. The role of cerebellar circuitry alterations in the pathophysiology of autism spectrum disorders. Front Neurosci. 2015;9:296. Scholar
  18. 18.
    Reeber SL, Otis TS, Sillitoe RV. New roles for the cerebellum in health and disease. Front Syst Neurosci. 2013;7:83. Scholar
  19. 19.
    Marien P, van Dun K, Verhoeven J. Cerebellum and apraxia. Cerebellum. 2015;14(1):39–42. Scholar
  20. 20.
    Hatten ME. Central nervous system neuronal migration. Annu Rev Neurosci. 1999;22(1):511–39. Scholar
  21. 21.
    Wang VY, Zoghbi HY. Genetic regulation of cerebellar development. Nat Rev Neurosci. 2001;2(7):484–91. Scholar
  22. 22.
    Leto K, Arancillo M, Becker EB, Buffo A, Chiang C, Ding B, et al. Consensus paper: cerebellar development. Cerebellum. 2016;15(6):789–828. Scholar
  23. 23.
    Hall ZJ, Street SE, Healy SD. The evolution of cerebellum structure correlates with nest complexity. Biol Lett. 2013;9(6):20130687. Scholar
  24. 24.
    Iwaniuk AN, Hurd PL, Wylie DR. Comparative morphology of the avian cerebellum: I. degree of foliation. Brain Behav Evol. 2006;68(1):45–62. Scholar
  25. 25.
    Lisney TJ, Yopak KE, Montgomery JC, Collin SP. Variation in brain organization and cerebellar foliation in chondrichthyans: batoids. Brain Behav Evol. 2008;72(4):262–82. Scholar
  26. 26.
    Yopak KE, Lisney TJ, Darlington RB, Collin SP, Montgomery JC, Finlay BL. A conserved pattern of brain scaling from sharks to primates. Proc Natl Acad Sci U S A. 2010;107(29):12946–51. Scholar
  27. 27.
    Eiraku M, Tohgo A, Ono K, Kaneko M, Fujishima K, Hirano T, et al. DNER acts as a neuron-specific notch ligand during Bergmann glial development. Nat Neurosci. 2005;8(7):873–80. Scholar
  28. 28.
    Hiraoka Y, Komine O, Nagaoka M, Bai N, Hozumi K, Tanaka K. Delta-like 1 regulates Bergmann glial monolayer formation during cerebellar development. Mol Brain. 2013;6(1):25. Scholar
  29. 29.
    Komine O, Nagaoka M, Watase K, Gutmann DH, Tanigaki K, Honjo T, et al. The monolayer formation of Bergmann glial cells is regulated by notch/RBP-J signaling. Dev Biol. 2007;311(1):238–50. Scholar
  30. 30.
    Kuang Y, Liu Q, Shu X, Zhang C, Huang N, Li J, et al. Dicer1 and MiR-9 are required for proper Notch1 signaling and the Bergmann glial phenotype in the developing mouse cerebellum. Glia. 2012;60(11):1734–46. Scholar
  31. 31.
    Weller M, Krautler N, Mantei N, Suter U, Taylor V. Jagged1 ablation results in cerebellar granule cell migration defects and depletion of Bergmann glia. Dev Neurosci. 2006;28(1-2):70–80. Scholar
  32. 32.
    Patten BA, Peyrin JM, Weinmaster G, Corfas G. Sequential signaling through Notch1 and erbB receptors mediates radial glia differentiation. J Neurosci. 2003;23(14):6132–40.PubMedGoogle Scholar
  33. 33.
    Sathyamurthy A, Yin DM, Barik A, Shen C, Bean JC, Figueiredo D, et al. ERBB3-mediated regulation of Bergmann glia proliferation in cerebellar lamination. Development. 2015;142(3):522–32. Scholar
  34. 34.
    Rio C, Rieff HI, Qi P, Khurana TS, Corfas G. Neuregulin and erbB receptors play a critical role in neuronal migration. Neuron. 1997;19(1):39–50. Scholar
  35. 35.
    Fauquier T, Chatonnet F, Picou F, Richard S, Fossat N, Aguilera N, et al. Purkinje cells and Bergmann glia are primary targets of the TRalpha1 thyroid hormone receptor during mouse cerebellum postnatal development. Development. 2014;141(1):166–75. Scholar
  36. 36.
    Belvindrah R, Nalbant P, Ding S, Wu C, Bokoch GM, Muller U. Integrin-linked kinase regulates Bergmann glial differentiation during cerebellar development. Mol Cell Neurosci. 2006;33(2):109–25. Scholar
  37. 37.
    Frick A, Grammel D, Schmidt F, Poschl J, Priller M, Pagella P, et al. Proper cerebellar development requires expression of beta1-integrin in Bergmann glia, but not in granule neurons. Glia. 2012;60(5):820–32. Scholar
  38. 38.
    Qiu Z, Cang Y, Goff SP. Abl family tyrosine kinases are essential for basement membrane integrity and cortical lamination in the cerebellum. J Neurosci. 2010;30(43):14430–9. Scholar
  39. 39.
    Yue Q, Groszer M, Gil JS, Berk AJ, Messing A, Wu H, et al. PTEN deletion in Bergmann glia leads to premature differentiation and affects laminar organization. Development. 2005;132(14):3281–91. Scholar
  40. 40.
    Dahmane N, Ruiz I, Altaba A. Sonic hedgehog regulates the growth and patterning of the cerebellum. Development. 1999;126(14):3089–100.PubMedGoogle Scholar
  41. 41.
    Mecklenburg N, Martinez-Lopez JE, Moreno-Bravo JA, Perez-Balaguer A, Puelles E, Martinez S. Growth and differentiation factor 10 (Gdf10) is involved in Bergmann glial cell development under Shh regulation. Glia. 2014;62(10):1713–23. Scholar
  42. 42.
    Wen J, Yang HB, Zhou B, Lou HF, Duan S. Beta-catenin is critical for cerebellar foliation and lamination. PLoS One. 2013;8(5):e64451. Scholar
  43. 43.
    Wang X, Tsai JW, LaMonica B, Kriegstein AR. A new subtype of progenitor cell in the mouse embryonic neocortex. Nat Neurosci. 2011;14(5):555–61. Scholar
  44. 44.
    Lin Y, Chen L, Lin C, Luo Y, Tsai RY, Wang F. Neuron-derived FGF9 is essential for scaffold formation of Bergmann radial fibers and migration of granule neurons in the cerebellum. Dev Biol. 2009;329(1):44–54. Scholar
  45. 45.
    Meier F, Giesert F, Delic S, Faus-Kessler T, Matheus F, Simeone A, et al. FGF/FGFR2 signaling regulates the generation and correct positioning of Bergmann glia cells in the developing mouse cerebellum. PLoS One. 2014;9(7):e101124. Scholar
  46. 46.
    Smith KM, Maragnoli ME, Phull PM, Tran KM, Choubey L, Vaccarino FM. Fgfr1 inactivation in the mouse telencephalon results in impaired maturation of interneurons expressing parvalbumin. PLoS One. 2014;9(8):e103696. Scholar
  47. 47.
    Grossmann KS, Rosario M, Birchmeier C, Birchmeier W. The tyrosine phosphatase Shp2 in development and cancer. Adv Cancer Res. 2010;106:53–89. Scholar
  48. 48.
    Feng GS. Shp2-mediated molecular signaling in control of embryonic stem cell self-renewal and differentiation. Cell Res. 2007;17(1):37–41. Scholar
  49. 49.
    Gauthier AS, Furstoss O, Araki T, Chan R, Neel BG, Kaplan DR, et al. Control of CNS cell-fate decisions by SHP-2 and its dysregulation in Noonan syndrome. Neuron. 2007;54(2):245–62. Scholar
  50. 50.
    Ke Y, Zhang EE, Hagihara K, Wu D, Pang Y, Klein R, et al. Deletion of Shp2 in the brain leads to defective proliferation and differentiation in neural stem cells and early postnatal lethality. Mol Cell Biol. 2007;27(19):6706–17. Scholar
  51. 51.
    Hagihara K, Zhang EE, Ke YH, Liu G, Liu JJ, Rao Y, et al. Shp2 acts downstream of SDF-1alpha/CXCR4 in guiding granule cell migration during cerebellar development. Dev Biol. 2009;334(1):276–84. Scholar
  52. 52.
    Li K, Leung AW, Guo Q, Yang W, Li JY. Shp2-dependent ERK signaling is essential for induction of Bergmann glia and foliation of the cerebellum. J Neurosci. 2014;34(3):922–31. Scholar
  53. 53.
    Heng X, Guo Q, Leung AW, Li JY. Analogous mechanism regulating formation of neocortical basal radial glia and cerebellar Bergmann glia. Elife. 2017; 6.Google Scholar
  54. 54.
    Yaguchi Y, Yu T, Ahmed MU, Berry M, Mason I, Basson MA. Fibroblast growth factor (FGF) gene expression in the developing cerebellum suggests multiple roles for FGF signaling during cerebellar morphogenesis and development. Dev Dyn. 2009;238(8):2058–72. Scholar
  55. 55.
    Mao J, McGlinn E, Huang P, Tabin CJ, McMahon AP. Fgf-dependent Etv4/5 activity is required for posterior restriction of sonic hedgehog and promoting outgrowth of the vertebrate limb. Dev Cell. 2009;16(4):600–6. Scholar
  56. 56.
    Zhang Z, Verheyden JM, Hassell JA, Sun X. FGF-regulated Etv genes are essential for repressing Shh expression in mouse limb buds. Dev Cell. 2009;16(4):607–13. Scholar
  57. 57.
    Sudarov A, Joyner AL. Cerebellum morphogenesis: the foliation pattern is orchestrated by multi-cellular anchoring centers. Neural Dev. 2007;2(1):26. Scholar
  58. 58.
    Ma S, Kwon HJ, Huang Z. Ric-8a, a guanine nucleotide exchange factor for heterotrimeric G proteins, regulates bergmann glia-basement membrane adhesion during cerebellar foliation. J Neurosci. 2012;32(43):14979–93. Scholar
  59. 59.
    Mills J, Niewmierzycka A, Oloumi A, Rico B, St-Arnaud R, Mackenzie IR, et al. Critical role of integrin-linked kinase in granule cell precursor proliferation and cerebellar development. J Neurosci. 2006;26(3):830–40. Scholar
  60. 60.
    Qu Q, Smith FI. Neuronal migration defects in cerebellum of the Largemyd mouse are associated with disruptions in Bergmann glia organization and delayed migration of granule neurons. Cerebellum. 2005;4(4):261–70. Scholar
  61. 61.
    Kaartinen V, Gonzalez-Gomez I, Voncken JW, Haataja L, Faure E, Nagy A, et al. Abnormal function of astroglia lacking Abr and Bcr RacGAPs. Development. 2001;128(21):4217–27.PubMedGoogle Scholar
  62. 62.
    Delaney CL, Brenner M, Messing A. Conditional ablation of cerebellar astrocytes in postnatal transgenic mice. J Neurosci. 1996;16(21):6908–18.PubMedGoogle Scholar
  63. 63.
    Hoser M, Baader SL, Bosl MR, Ihmer A, Wegner M, Sock E. Prolonged glial expression of Sox4 in the CNS leads to architectural cerebellar defects and ataxia. J Neurosci. 2007;27(20):5495–505. Scholar
  64. 64.
    Gotz M, Huttner WB. The cell biology of neurogenesis. Nat Rev Mol Cell Biol. 2005;6(10):777–88. Scholar
  65. 65.
    Fietz SA, Kelava I, Vogt J, Wilsch-Brauninger M, Stenzel D, Fish JL, et al. OSVZ progenitors of human and ferret neocortex are epithelial-like and expand by integrin signaling. Nat Neurosci. 2010;13(6):690–9. Scholar
  66. 66.
    Hansen DV, Lui JH, Parker PR, Kriegstein AR. Neurogenic radial glia in the outer subventricular zone of human neocortex. Nature. 2010;464(7288):554–61. Scholar
  67. 67.
    Reillo I, de Juan Romero C, Garcia-Cabezas MA, Borrell V. A role for intermediate radial glia in the tangential expansion of the mammalian cerebral cortex. Cereb Cortex. 2011;21(7):1674–94. Scholar
  68. 68.
    Martinez-Martinez MA, De Juan Romero C, Fernandez V, Cardenas A, Gotz M, Borrell V. A restricted period for formation of outer subventricular zone defined by Cdh1 and Trnp1 levels. Nat Commun. 2016;7:11812. Scholar
  69. 69.
    Shitamukai A, Konno D, Matsuzaki F. Oblique radial glial divisions in the developing mouse neocortex induce self-renewing progenitors outside the germinal zone that resemble primate outer subventricular zone progenitors. J Neurosci. 2011;31(10):3683–95. Scholar
  70. 70.
    Borrell V, Gotz M. Role of radial glial cells in cerebral cortex folding. Curr Opin Neurobiol. 2014;27:39–46. Scholar
  71. 71.
    Dehay C, Kennedy H, Kosik KS. The outer subventricular zone and primate-specific cortical complexification. Neuron. 2015;85(4):683–94. Scholar
  72. 72.
    Fernandez V, Llinares-Benadero C, Borrell V. Cerebral cortex expansion and folding: what have we learned? EMBO J. 2016;35(10):1021–44.  10.15252/embj.201593701.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Fietz SA, Huttner WB. Cortical progenitor expansion, self-renewal and neurogenesis—a polarized perspective. Curr Opin Neurobiol. 2011;21(1):23–35. Scholar
  74. 74.
    Geschwind DH, Rakic P. Cortical evolution: judge the brain by its cover. Neuron. 2013;80(3):633–47. Scholar
  75. 75.
    Lui JH, Nowakowski TJ, Pollen AA, Javaherian A, Kriegstein AR, Oldham MC. Radial glia require PDGFD-PDGFRbeta signalling in human but not mouse neocortex. Nature. 2014;515(7526):264–8. Scholar
  76. 76.
    Nonaka-Kinoshita M, Reillo I, Artegiani B, Martinez-Martinez MA, Nelson M, Borrell V, et al. Regulation of cerebral cortex size and folding by expansion of basal progenitors. EMBO J. 2013;32(13):1817–28. Scholar
  77. 77.
    Reillo I, Borrell V. Germinal zones in the developing cerebral cortex of ferret: ontogeny, cell cycle kinetics, and diversity of progenitors. Cereb Cortex. 2012;22(9):2039–54. Scholar
  78. 78.
    Pollen AA, Nowakowski TJ, Chen J, Retallack H, Sandoval-Espinosa C, Nicholas CR, et al. Molecular identity of human outer radial glia during cortical development. Cell. 2015;163(1):55–67. Scholar
  79. 79.
    Thomsen ER, Mich JK, Yao Z, Hodge RD, Doyle AM, Jang S, et al. Fixed single-cell transcriptomic characterization of human radial glial diversity. Nat Methods. 2016;13(1):87–93. Scholar
  80. 80.
    Pollen AA, Nowakowski TJ, Shuga J, Wang X, Leyrat AA, Lui JH, et al. Low-coverage single-cell mRNA sequencing reveals cellular heterogeneity and activated signaling pathways in developing cerebral cortex. Nat Biotechnol. 2014;32(10):1053–8. Scholar
  81. 81.
    Tang N, Marshall WF, McMahon M, Metzger RJ, Martin GR. Control of mitotic spindle angle by the RAS-regulated ERK1/2 pathway determines lung tube shape. Science. 2011;333(6040):342–5. Scholar
  82. 82.
    LaMonica BE, Lui JH, Hansen DV, Kriegstein AR. Mitotic spindle orientation predicts outer radial glial cell generation in human neocortex. Nat Commun. 2013;4:1665. Scholar
  83. 83.
    Hevner RF, Haydar TF. The (not necessarily) convoluted role of basal radial glia in cortical neurogenesis. Cereb Cortex. 2012;22(2):465–8. Scholar
  84. 84.
    Kelava I, Reillo I, Murayama AY, Kalinka AT, Stenzel D, Tomancak P, et al. Abundant occurrence of basal radial glia in the subventricular zone of embryonic neocortex of a lissencephalic primate, the common marmoset Callithrix jacchus. Cereb Cortex. 2012;22(2):469–81. Scholar

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Authors and Affiliations

  1. 1.Department of Genetics and Yale Stem Cell CenterYale UniversityNew HavenUSA
  2. 2.Department of Genetics and Genome SciencesUniversity of Connecticut School of MedicineFarmingtonUSA
  3. 3.Institute for Systems GenomicsUniversity of ConnecticutFarmingtonUSA

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