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Granule neuron precursor cell proliferation is regulated by NFIX and intersectin 1 during postnatal cerebellar development

  • James Fraser
  • Alexandra Essebier
  • Alexander S. Brown
  • Raul Ayala Davila
  • Ameet S. Sengar
  • YuShan Tu
  • Kathleen S. Ensbey
  • Bryan W. Day
  • Matthew P. Scott
  • Richard M. Gronostajski
  • Brandon J. Wainwright
  • Mikael Boden
  • Tracey J. Harvey
  • Michael Piper
Original Article

Abstract

Cerebellar granule neurons are the most numerous neuronal subtype in the central nervous system. Within the developing cerebellum, these neurons are derived from a population of progenitor cells found within the external granule layer of the cerebellar anlage, namely the cerebellar granule neuron precursors (GNPs). The timely proliferation and differentiation of these precursor cells, which, in rodents occurs predominantly in the postnatal period, is tightly controlled to ensure the normal morphogenesis of the cerebellum. Despite this, our understanding of the factors mediating how GNP differentiation is controlled remains limited. Here, we reveal that the transcription factor nuclear factor I X (NFIX) plays an important role in this process. Mice lacking Nfix exhibit reduced numbers of GNPs during early postnatal development, but elevated numbers of these cells at postnatal day 15. Moreover, Nfix−/− GNPs exhibit increased proliferation when cultured in vitro, suggestive of a role for NFIX in promoting GNP differentiation. At a mechanistic level, profiling analyses using both ChIP-seq and RNA-seq identified the actin-associated factor intersectin 1 as a downstream target of NFIX during cerebellar development. In support of this, mice lacking intersectin 1 also displayed delayed GNP differentiation. Collectively, these findings highlight a key role for NFIX and intersectin 1 in the regulation of cerebellar development.

Keywords

NFIX Cerebellum External granular layer Granule neuron 

Notes

Acknowledgements

This work was supported by a Cancer Council Queensland Grant (MP), an Australian Research Council grants (DP160100368, DP180100017 to MP) and NYSTEM grants (CO30133 and C30290GG to RMG). MP was supported by a fellowship (Australian Research Council Future Fellowship; FT120100170). JF and AE were supported by Australian Postgraduate Awards. ASB was supported by Ruth L. Kirschstein NRSA F32 GM105227.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • James Fraser
    • 1
  • Alexandra Essebier
    • 2
  • Alexander S. Brown
    • 5
  • Raul Ayala Davila
    • 1
  • Ameet S. Sengar
    • 6
  • YuShan Tu
    • 6
  • Kathleen S. Ensbey
    • 7
  • Bryan W. Day
    • 7
  • Matthew P. Scott
    • 5
  • Richard M. Gronostajski
    • 8
  • Brandon J. Wainwright
    • 3
  • Mikael Boden
    • 2
  • Tracey J. Harvey
    • 1
  • Michael Piper
    • 1
    • 4
  1. 1.The School of Biomedical SciencesThe University of QueenslandBrisbaneAustralia
  2. 2.The School of Chemistry and Molecular BioscienceThe University of QueenslandBrisbaneAustralia
  3. 3.Institute for Molecular BioscienceThe University of QueenslandBrisbaneAustralia
  4. 4.Queensland Brain InstituteThe University of QueenslandBrisbaneAustralia
  5. 5.Department of Developmental BiologyStanford University School of MedicineStanfordUSA
  6. 6.Program in Neurosciences & Mental HealthThe Hospital for Sick ChildrenTorontoCanada
  7. 7.Cell and Molecular Biology Department, Translational Brain Cancer Research LaboratoryQIMR Berghofer MRIBrisbaneAustralia
  8. 8.Department of Biochemistry, Program in Genetics, Genomics and Bioinformatics, Center of Excellence in Bioinformatics and Life SciencesState University of New York at BuffaloBuffaloUSA

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