Skip to main content
Log in

The Treasury of the Commons: Making Use of Public Gene Expression Resources to Better Characterize the Molecular Diversity of Inhibitory Interneurons in the Cerebellar Cortex

  • Published:
The Cerebellum Aims and scope Submit manuscript

Abstract

We mined the Allen Mouse Brain Atlas for genes expressed in cerebellar cortical inhibitory interneurons that would allow identification and possibly distinction of these cells. We identified some 90 genes that are highly expressed in specific subsets of cerebellar cortical inhibitory interneurons or various combinations thereof. Four genes are exclusively expressed, within the cerebellar cortex, in molecular layer interneurons, and ten genes label exclusively inhibitory interneurons in the granule cell layer or subsets thereof. Differential expression of many of these genes in cells residing in the lower versus the upper molecular layer provides evidence that these cells, traditionally referred to as basket and stellate cells, are indeed molecularly distinct. Two genes could be identified as novel markers for unipolar brush cells. Intersection of these data with embryonic expression patterns as documented in the genepaint repository does not support a hierarchical model of cerebellar interneuron development, but may be more easily reconciled with the view that cerebellar inhibitory interneurons derive from a common precursor pool from which they are specified only late into their development. The novel markers identified here should prove useful for probing the timing and mechanisms supporting cerebellar cortical interneuron specification and diversification.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.

Similar content being viewed by others

References

  1. Hardin G (1968) The tragedy of the commons. Science 162:1243–1248

    Article  CAS  Google Scholar 

  2. Larouche M, Hawkes R (2006) From clusters to stripes: the developmental origins of adult cerebellar compartmentation. Cerebellum 5:77–88

    Article  CAS  PubMed  Google Scholar 

  3. Oberdick J, Baader SL, Schilling K (1998) From zebra stripes to postal zones: deciphering patterns of gene expression in the cerebellum. TINS 21:383–391

    CAS  PubMed  Google Scholar 

  4. Schilling K, Schmidt HHHW, Baader SL (1994) Nitric oxide synthase expression reveals compartments of cerebellar granule cells and suggests a role for mossy fibers in their development. Neuroscience 59:893–903

    Article  CAS  PubMed  Google Scholar 

  5. Oberdick J, Smeyne RJ, Mann JR et al (1990) A promoter that drives transgene expression in cerebellar Purkinje and retinal bipolar neurons. Science 248:223–226

    Article  CAS  PubMed  Google Scholar 

  6. Bahn S, Jones A, Wisden W (1997) Directing gene expression to cerebellar granule cells using γ-aminobutyric acid type A receptor α6 subunit transgenes. Proc Natl Acad Sci U S A 94:9417–9421

    Article  CAS  PubMed  Google Scholar 

  7. Oberdick J, Schilling K, Smeyne RJ et al (1993) Control of segment-like patterns of gene expression in the mouse cerebellum. Neuron 10:1007–1018

    Article  CAS  PubMed  Google Scholar 

  8. Bahn S, Wisden W, Dunnett SB et al (1999) The intrinsic specification of γ-aminobutyric acid type A receptor α6 subunit gene expression in cerebellar granule cells. Eur J NeuroSci 11:2194–2198

    Article  CAS  PubMed  Google Scholar 

  9. Wulff P, Goetz T, Leppa E et al (2007) From synapse to behavior: rapid modulation of defined neuronal types with engineered GABAA receptors. Nat Neurosci 10:923–929

    Article  CAS  PubMed  Google Scholar 

  10. De Zeeuw CI, Hansel C, Bian F et al (1998) Expression of a protein kinase C inhibitor in Purkinje cells blocks cerebellar long term depression and adaption of the vestibulo-ocular reflex. Neuron 20:495–508

    Article  PubMed  Google Scholar 

  11. Schilling K, Oberdick J, Rossi F et al (2008) Besides Purkinje cells and granule neurons: an appraisal of the cell biology of the interneurons of the cerebellar cortex. Histochem Cell Biol 130:601–615

    Article  CAS  PubMed  Google Scholar 

  12. Leto K, Bartolini A, Rossi F (2008) Development of cerebellar GABAergic interneurons: origin and shaping of the “minibrain” local connections. Cerebellum 7:523–529

    Article  CAS  PubMed  Google Scholar 

  13. Simat M, Parpan F, Fritschy JM (2007) Heterogeneity of glycinergic and gabaergic interneurons in the granule cell layer of mouse cerebellum. J Comp Neurol 500:71–83

    Article  CAS  PubMed  Google Scholar 

  14. Maricich SM, Herrup K (1999) Pax-2 expression defines a subset of GABAergic interneurons and their precursors in the developing murine cerebellum. J Neurobiol 41:281–294

    Article  CAS  PubMed  Google Scholar 

  15. Carletti B, Williams IM, Leto K et al (2008) Time constraints and positional cues in the developing cerebellum regulate Purkinje cell placement in the cortical architecture. Dev Biol 317:147–160

    Article  CAS  PubMed  Google Scholar 

  16. Weisheit G, Gliem M, Endl E et al (2006) Postnatal development of the murine cerebellar cortex: formation and early dispersal of basket, stellate and Golgi neurons. Eur J NeuroSci 24:466–478

    Article  PubMed  Google Scholar 

  17. Glassmann A, Topka S, Wang-Eckardt L et al (2009) Basic molecular fingerprinting of immature cerebellar cortical inhibitory interneurons and their precursors. Neuroscience 159:69–82

    Article  CAS  PubMed  Google Scholar 

  18. Lein ES, Hawrylycz MJ, Ao N et al (2007) Genome-wide atlas of gene expression in the adult mouse brain. Nature 445:168–176

    Article  CAS  PubMed  Google Scholar 

  19. Visel A, Thaller C, Eichele G (2004) GenePaint.org: an atlas of gene expression patterns in the mouse embryo. Nucleic Acids Res 32:D552–D556

    Article  CAS  PubMed  Google Scholar 

  20. Syverud K, Chinga G, Johnsen PO et al (2007) Analysis of lint particles from full-scale printing trials. Appita J 60:286–290

    Google Scholar 

  21. Chizhikov VV, Lindgren AG, Currle DS et al (2006) The roof plate regulates cerebellar cell-type specification and proliferation. Development 133:2793–2804

    Article  CAS  PubMed  Google Scholar 

  22. Zordan P, Croci L, Hawkes R et al (2008) Comparative analysis of proneural gene expression in the embryonic cerebellum. Dev Dyn 237:1726–1735

    Article  CAS  PubMed  Google Scholar 

  23. Boutros PC, Okey AB (2005) Unsupervised pattern recognition: an introduction to the whys and wherefores of clustering microarray data. Brief Bioinform 6:331–343

    Article  CAS  PubMed  Google Scholar 

  24. R Development Core Team (2008) R: a language and environment for statistical computing. R Foundation for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing

  25. Geurts FJ, De Schutter E, Dieudonne S (2003) Unraveling the cerebellar cortex: cytology and cellular physiology of large-sized interneurons in the granular layer. Cerebellum 2:290–299

    Article  PubMed  Google Scholar 

  26. Tanaka I, Ezure K (2004) Overall distribution of GLYT2 mRNA-containing versus GAD67 mRNA-containing neurons and colocalization of both mRNAs in midbrain, pons, and cerebellum in rats. Neurosci Res 49:165–178

    Article  CAS  PubMed  Google Scholar 

  27. Zeilhofer HU, Studler B, Arabadzisz D et al (2005) Glycinergic neurons expressing enhanced green fluorescent protein in bacterial artificial chromosome transgenic mice. J Comp Neurol 482:123–141

    Article  CAS  PubMed  Google Scholar 

  28. Manova K, Bachvarova RF, Huang EJ et al (1992) c-kit receptor and ligand expression in postnatal development of the mouse cerebellum suggests a function for c-kit in inhibitory interneurons. J Neurosci 12:4663–4676

    CAS  PubMed  Google Scholar 

  29. Ino H (2004) Immunohistochemical characterization of the orphan nuclear receptor ROR alpha in the mouse nervous system. J Histochem Cytochem 52:311–323

    Article  CAS  PubMed  Google Scholar 

  30. Viltono L, Patrizi A, Fritschy JM et al (2008) Synaptogenesis in the cerebellar cortex: differential regulation of gephyrin and GABAA receptors at somatic and dendritic synapses of Purkinje cells. J Comp Neurol 508:579–591

    Article  PubMed  Google Scholar 

  31. Chan-Palay V (1977) Cerebellar dentate nucleus. Organization, cytology and transmitters. Springer, Berlin

    Google Scholar 

  32. Uusisaari M, Obata K, Knopfel T (2007) Morphological and electrophysiological properties of GABAergic and non-GABAergic cells in the deep cerebellar nuclei. J Neurophysiol 97:901–911

    Article  CAS  PubMed  Google Scholar 

  33. Palay SL, Chan-Palay V (1974) Cerebellar cortex. Cytology and organization. Springer, Berlin

    Google Scholar 

  34. Wojcik SM, Katsurabayashi S, Guillemin I et al (2006) A shared vesicular carrier allows synaptic corelease of GABA and glycine. Neuron 50:575–587

    Article  CAS  PubMed  Google Scholar 

  35. Sneath PH, Sokal RR (1973) Numerical taxonomy. Freeman, San Francisco

    Google Scholar 

  36. Finch H, Huyhn H (2000) Comparison of similarity measures in cluster analysis with binary data. Paper presented at the Annual Meeting of the American Educational Research Association, New Orleans, 2000. Available at http://eric.ed.gov

  37. Dino MR, Willard FH, Mugnaini E (1999) Distribution of unipolar brush cells and other calretinin immunoreactive components in the mammalian cerebellar cortex. J Neurocytol 28:99–123

    Article  CAS  PubMed  Google Scholar 

  38. Matter K, Balda MS (2003) Holey barrier: claudins and the regulation of brain endothelial permeability. J Cell Biol 161:459–460

    Article  CAS  PubMed  Google Scholar 

  39. Alva JA, Zovein AC, Monvoisin A et al (2006) VE-cadherin-Cre-recombinase transgenic mouse: a tool for lineage analysis and gene deletion in endothelial cells. Dev Dyn 235:759–767

    Article  CAS  PubMed  Google Scholar 

  40. Doyle JP, Dougherty JD, Heiman M et al (2008) Application of a translational profiling approach for the comparative analysis of CNS cell types. Cell 135:749–762

    Article  CAS  PubMed  Google Scholar 

  41. Ashton JC, Appleton I, Darlington CL et al (2004) Immunohistochemical localization of cannabinoid CB1 receptor in inhibitory interneurons in the cerebellum. Cerebellum 3:222–226

    Article  CAS  PubMed  Google Scholar 

  42. Simat M, Ambrosetti L, Lardi-Studler B et al (2007) GABAergic synaptogenesis marks the onset of differentiation of basket and stellate cells in mouse cerebellum. Eur J NeuroSci 26:2239–2256

    Article  PubMed  Google Scholar 

  43. Sultan F, Czubayko U, Thier P (2003) Morphological classification of the rat lateral cerebellar nuclear neurons by principal component analysis. J Comp Neurol 455:139–155

    Article  PubMed  Google Scholar 

  44. Lingueglia E (2007) Acid-sensing ion channels in sensory perception. J Biol Chem 282:17325–17329

    Article  CAS  PubMed  Google Scholar 

  45. Ten Hagen KG, Fritz TA, Tabak LA (2003) All in the family: the UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferases. Glycobiology 13:1R–16R

    Article  PubMed  Google Scholar 

  46. Haltiwanger RS, Lowe JB (2004) Role of glycosylation in development. Annu Rev Biochem 73:491–537 491-537

    Article  CAS  PubMed  Google Scholar 

  47. Herr P, Korniychuk G, Yamamoto Y et al (2008) Regulation of TGF-(beta) signalling by N-acetylgalactosaminyltransferase-like 1. Development 135:1813–1822

    Article  CAS  PubMed  Google Scholar 

  48. Jaffrey SR, Snowman AM, Eliasson MJL et al (1998) CAPON: a protein associated with neuronal nitric oxide synthase that regulates its interactions with PSD95. Neuron 20:115–124

    Article  CAS  PubMed  Google Scholar 

  49. Kong J, Tung VW, Aghajanian J et al (1998) Antagonistic roles of neurofilament subunits NF-H and NF-M against NF-L in shaping dendritic arborization in spinal motor neurons. J Cell Biol 140:1167–1176

    Article  CAS  PubMed  Google Scholar 

  50. Xu Z, Marszalek JR, Lee MK et al (1996) Subunit composition of neurofilaments specifies axonal diameter. J Cell Biol 133:1061–1069

    Article  CAS  PubMed  Google Scholar 

  51. Sternberger LA, Sternberger NH (1983) Monoclonal antibodies distinguish phosphorylated and nonphosphorylated forms of neurofilaments in situ. Proc Natl Acad Sci U S A 80:6126–6130

    Article  CAS  PubMed  Google Scholar 

  52. Riederer BM, Porchet R, Marugg RA (1996) Differential expression and modification of neurofilament triplet proteins during cat cerebellar development. J Comp Neurol 364:704–717

    Article  CAS  PubMed  Google Scholar 

  53. Rubina K, Kalinina N, Potekhina A et al (2007) T-cadherin suppresses angiogenesis in vivo by inhibiting migration of endothelial cells. Angiogenesis 10:183–195

    Article  CAS  PubMed  Google Scholar 

  54. Bai S, Ghoshal K, Jacob ST (2006) Identification of T-cadherin as a novel target of DNA methyltransferase 3B and its role in the suppression of nerve growth factor-mediated neurite outgrowth in PC12 cells. J Biol Chem 281:13604–13611

    Article  CAS  PubMed  Google Scholar 

  55. D'Angelo E (2008) The critical role of Golgi cells in regulating spatio-temporal integration and plasticity at the cerebellum input stage. Front Neurosci 2:35–46

    Article  PubMed  Google Scholar 

  56. Roggeri L, Rivieccio B, Rossi P et al (2008) Tactile stimulation evokes long-term synaptic plasticity in the granular layer of cerebellum. J Neurosci 28:6354–6359

    Article  CAS  PubMed  Google Scholar 

  57. Chandra S, Fornai F, Kwon HB et al (2004) Double-knockout mice for alpha- and beta-synucleins: effect on synaptic functions. Proc Natl Acad Sci U S A 101:14966–14971

    Article  CAS  PubMed  Google Scholar 

  58. Gureviciene I, Gurevicius K, Tanila H (2007) Role of alpha-synuclein in synaptic glutamate release. Neurobiol Dis 28:83–89

    Article  CAS  PubMed  Google Scholar 

  59. Huang WC, Young JS, Glitsch MD (2007) Changes in TRPC channel expression during postnatal development of cerebellar neurons. Cell Calcium 42:1–10

    Article  CAS  PubMed  Google Scholar 

  60. Hartmann J, Dragicevic E, Adelsberger H et al (2008) TRPC3 channels are required for synaptic transmission and motor coordination. Neuron 59:392–398

    Article  CAS  PubMed  Google Scholar 

  61. Leto K, Bartolini A, Yanagawa Y, Obata K, Magrassi L, Schilling K, Rossi F (2009) Laminar fate and phenotype specification of cerebellar GABAergic interneurons. J Neurosci 29:7079–7091

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Dr. Gary Chinga Carrasco (Trondheim, Norway) for his help with the ShapeDescriptor1 plugin. We would also like to thank the people behind the Allen Brain Atlas for establishing this database and making it publicly available.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Karl Schilling.

Additional information

This title was inspired by the work of Garrett Hardin, “The Tragedy of the Commons” [1]; its modification should not be construed to indicate disagreement with this fundamental paper. Rather, our intention is to suggest an optimistic view of the future in which natural resources are managed with the kind of wisdom that led to the creation of the public informatics resources utilized herein.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schilling, K., Oberdick, J. The Treasury of the Commons: Making Use of Public Gene Expression Resources to Better Characterize the Molecular Diversity of Inhibitory Interneurons in the Cerebellar Cortex. Cerebellum 8, 477–489 (2009). https://doi.org/10.1007/s12311-009-0124-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12311-009-0124-6

Keywords

Navigation