The Cerebellum

, Volume 17, Issue 1, pp 62–71 | Cite as

Migration of Interneuron Precursors in the Nascent Cerebellar Cortex

  • Annika K. Wefers
  • Christian Haberlandt
  • Lachezar Surchev
  • Christian Steinhäuser
  • Ronald Jabs
  • Karl SchillingEmail author
Original Paper


The cerebellum arguably constitutes one of the best characterized central nervous circuits, and its structure, cellular function, and histogenesis have been described in exceptional quantitative detail. A notable exception to this is the development of its inhibitory interneurons, and in particular the extensive migrations of future basket and stellate cells. Here, we used acute slices from 8-day-old mice to assess the migration of Pax2-EGFP-tagged precursors of these cells en route to the molecular layer during their transit through the nascent cerebellar cortex. We document that movement of these cells is highly directed. Their speed and directional persistence are larger in the nascent granule cell layer than in the molecular layer. And they migrate periodically, with periods of effective, directed translocation separated by bouts of rather local movement. Finally, we document that the arrangement of these cells in the adult molecular layer is characterized by clustering. These data are discussed with a focus on potential generative mechanisms for the developmental pattern observed.


Cerebellum Inhibitory interneuron Cell migration Pax2 Development Mouse 



This work was supported by grants of the German Research Foundation [SPP1757: STE 552/5 to C.S., JA 942-1/2 to RJ] and the European Union [ERA-NET NEURON: BrIE to C.S.].

Compliance with Ethical Standards

Competing Interests

The authors declare that they have no competing interests.

Supplementary material

12311_2017_900_MOESM1_ESM.mp4 (9.9 mb)
Supplementary Movie 1 This movie shows translocation of several cells through the nascent cerebellar cortex. The border of the white matter is close to the right hand margin of the scene, that of the EGL close to the left hand margin. In the initial still image, the approximate position of the Purkinje cell layer is indicated by white dots. The three yellow arrowheads in this still mark Pax2 cells that migrate extensively. One of them is actually hidden underneath a large, immobile (Golgi) cell at the start of the scene. The red arrow indicates a group of Pax2 cells at the fringe of the white matter, one of which effectively migrates into the granule cell layer. The position of the perikarya of these cells is again marked with arrows in the still at the end of the scene. Next, cell tracks are shown, and the translocation of the cells’ centers of gravity defining these paths. Not that the speed of translocation varies considerably over the 4 h period shown, with phases of effective translocation interspersed with phases of low mobility. (MP4 10088 kb)


  1. 1.
    Baddeley A, Rubak E, Turner R. Spatial point patterns: methodology and applications with R. London: Chapman and Hall/CRC; 2015.Google Scholar
  2. 2.
    Bartumeus F, Da Luz MGE, Viswanathan GM, Catalan J. Animal search strategies: a quantitative random-walk analysis. Ecology. 2005;86:3078–87.CrossRefGoogle Scholar
  3. 3.
    Batschelet E. Circular statistics in biology. London. New York: Academic Press; 1981.Google Scholar
  4. 4.
    Cameron DB, Kasai K, Jiang Y, Hu T, Saeki Y, Komuro H. Four distinct phases of basket/stellate cell migration after entering their final destination (the molecular layer) in the developing cerebellum. Dev Biol. 2009;332:309–24.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Codling EA, Plank MJ, Benhamou S. Random walk models in biology. J R Soc Interface. 2008;5:813–34.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Consalez GG, Hawkes R. The compartmental restriction of cerebellar interneurons. Front Neural Circuits. 2013;6:123.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Goldowitz D, Hamre KM. The cells and molecules that make a cerebellum. TINS. 1998;21:375–82.PubMedGoogle Scholar
  8. 8.
    Jankowski J, Holst MI, Liebig C, Oberdick J, Baader SL. Engrailed-2 negatively regulates the onset of perinatal Purkinje cell differentiation. J Comp Neurol. 2004;472:87–99.CrossRefPubMedGoogle Scholar
  9. 9.
    Komuro H, Rakic P. Dynamics of granule cell migration: a confocal microscopy study in acute cerebellar slice preparations. J Neurosci. 1995;15:1110–20.PubMedGoogle Scholar
  10. 10.
    Koscheck T, Weyer A, Schilling RL, Schilling K. Morphological development and neurochemical differentiation of cerebellar inhibitory interneurons in microexplant cultures. Neuroscience. 2003;116:973–84.CrossRefPubMedGoogle Scholar
  11. 11.
    Lein ES, et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature. 2007;445:168–76.CrossRefPubMedGoogle Scholar
  12. 12.
    Leto K, Bartolini A, Yanagawa Y, Obata K, Magrassi L, Schilling K, et al. Laminar fate and phenotype specification of cerebellar GABAergic interneurons. J Neurosci. 2009;29:7079–91.CrossRefPubMedGoogle Scholar
  13. 13.
    Maricich SM, Herrup K. Pax-2 expression defines a subset of GABAergic interneurons and their precursors in the developing murine cerebellum. J Neurobiol. 1999;41:281–94.CrossRefPubMedGoogle Scholar
  14. 14.
    Michalet X. Mean square displacement analysis of single-particle trajectories with localization error: Brownian motion in an isotropic medium. Phys Rev E Stat Nonlinear Soft Matter Phys. 2010;82:041914.CrossRefGoogle Scholar
  15. 15.
    Neyman J, Scott EL. Statistical approach to problems of cosmology. J R Stat Soc Ser B Methodol. 1958;20:1–43.Google Scholar
  16. 16.
    Pfeffer PL, Payer B, Reim G, di Magliano MP, Busslinger M. The activation and maintenance of Pax2 expression at the mid-hindbrain boundary is controlled by separate enhancers. Development. 2002;129:307–18.PubMedGoogle Scholar
  17. 17.
    R Core Team. R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing (2017) ISBN 3–900051–07-0; URL
  18. 18.
    Rakic P. Neuron-glia relationship during granule cell migration in developing cerebellar cortex. A Golgi and electronmicroscopic study in maccacus rhesus. J Comp Neurol. 1971;141:283–312.CrossRefPubMedGoogle Scholar
  19. 19.
    Rakic P. Extrinsic cytological determinants of basket and stellate cell dendritic pattern in the cerebellar molecular layer. J Comp Neurol. 1972;146:335–54.CrossRefPubMedGoogle Scholar
  20. 20.
    Ramon y Cajal, S (1909) Histologie du système nerveux de l'homme et des vertébrés. II. Paris: A. Maloine.Google Scholar
  21. 21.
    Schettlinger K, Fried R, Gather U. Robust filters for intensive care monitoring: beyond the running median. Biomed Tech (Berl). 2006;51:49–56.CrossRefGoogle Scholar
  22. 22.
    Schilling K, Oberdick J, Rossi F, Baader SL. Besides Purkinje cells and granule neurons: an appraisal of the cell biology of the interneurons of the cerebellar cortex. Histochem Cell Biol. 2008;130:601–15.CrossRefPubMedGoogle Scholar
  23. 23.
    Simat M, Ambrosetti L, Lardi-Studler B, Fritschy JM. GABAergic synaptogenesis marks the onset of differentiation of basket and stellate cells in mouse cerebellum. Eur J Neurosci. 2007a;26:2239–56.CrossRefPubMedGoogle Scholar
  24. 24.
    Simat M, Parpan F, Fritschy JM. Heterogeneity of glycinergic and GABAergic interneurons in the granule cell layer of mouse cerebellum. J Comp Neurol. 2007b;500:71–83.CrossRefPubMedGoogle Scholar
  25. 25.
    Solecki DJ, Trivedi N, Govek EE, Kerekes RA, Gleason SS, Hatten ME. Myosin II motors and F-actin dynamics drive the coordinated movement of the centrosome and soma during CNS glial-guided neuronal migration. Neuron. 2009;63:63–80.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Valera AM, Binda F, Pawlowski SA, Dupont JL, Casella JF, Rothstein JD, et al. Stereotyped spatial patterns of functional synaptic connectivity in the cerebellar cortex. elife. 2016;5:e09862.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    van Lieshout MNM, Baddeley AJ. A nonparametric measure of spatial interaction in point patterns. Statistica Neerlandica. 1996;50:344–61.CrossRefGoogle Scholar
  28. 28.
    Wefers AK, Haberlandt C, Tekin NB, Fedorov DA, Timmermann A, van der Want JJL, et al. Synaptic input as a directional cue for migrating interneuron precursors. Development. 2017;144:4125–36.Google Scholar
  29. 29.
    Weisheit G, Gliem M, Endl E, Pfeffer PL, Busslinger M, Schilling K. Postnatal development of the murine cerebellar cortex: formation and early dispersal of basket, stellate and Golgi neurons. Eur J Neurosci. 2006;24:466–78.CrossRefPubMedGoogle Scholar
  30. 30.
    Yacubova E, Komuro H. Stage-specific control of neuronal migration by somatostatin. Nature. 2002;415:77–81.CrossRefPubMedGoogle Scholar
  31. 31.
    Yau CY, Loh JM. A generalization of the Neyman-Scott process. Stat Sin. 2012;22:1717–36.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  • Annika K. Wefers
    • 1
    • 2
    • 3
  • Christian Haberlandt
    • 2
  • Lachezar Surchev
    • 1
    • 4
  • Christian Steinhäuser
    • 2
  • Ronald Jabs
    • 2
  • Karl Schilling
    • 1
    Email author
  1. 1.Anatomisches Institut, Anatomie & ZellbiologieMedical Faculty of the University of BonnBonnGermany
  2. 2.Institut für Zelluläre NeurowissenschaftenMedical Faculty of the University of BonnBonnGermany
  3. 3.Department of Neuropathology, Institute of PathologyRuprecht-Karls-UniversityHeidelbergGermany
  4. 4.Department of Anatomy, Histology and EmbryologyMedical University SofiaSofiaBulgaria

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