Targets of the nuclear factor I regulon involved in early and late development of postmitotic cerebellar granule neurons

J Neurosci Res. 2010 Feb 1;88(2):258-65. doi: 10.1002/jnr.22199.


Recent studies have shown that the nuclear factor I (NFI) family controls multiple stages of the postmitotic differentiation of cerebellar granule neurons (CGNs). Regulation of cell-cell signaling is an integral part of this NFI program, which involves expression of the cell adhesion molecules N cadherin and ephrin B1 throughout postmitotic CGN development. Here, we identify two additional downstream targets of NFI that are involved in extracellular CGN interactions. The cell adhesion molecule Tag-1 is highly enriched in CGNs undergoing parallel fiber formation and is down-regulated prior to onset of radial migration. We found that Tag-1 expression was strongly reduced by NFI dominant repression in immature primary CGNs and in the cerebella of E18 Nfib-null mice. Transient transfection and chromatin immunoprecipitation suggested that the Tag-1 gene is directly regulated by NFI. Furthermore, functional, Nfi knockout and chromatin immunoprecipitation studies implicated Wnt7a as a direct target of NFI in maturing CGNs. Wnt7a is secreted by developing CGNs and is required for maturation of mossy fiber-CGN synaptic rosettes. Consistent with this, synapsin I was greatly reduced within the internal granule cell layer of P17 Nfia-null mice. These findings indicated that NFI controls CGN postmitotic maturation through a combination of extracellular signaling molecules that operate either continuously to regulate multiple stages of development (N cadherin and ephrin B1) or primarily at early (Tag-1) or late (Wnt7a) maturation steps. They also illustrate the importance of NFI as a critical link between cell-intrinsic mechanisms and cell-cell interactions in the development of the mouse cerebellum.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cadherins / metabolism
  • Cell Adhesion Molecules, Neuronal / metabolism
  • Cell Communication / physiology
  • Cells, Cultured
  • Cerebellum / embryology
  • Cerebellum / growth & development
  • Cerebellum / physiology*
  • Chromatin / metabolism
  • Contactin 2
  • Ephrin-B1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitosis
  • NFI Transcription Factors / genetics*
  • NFI Transcription Factors / metabolism
  • Neurons / physiology*
  • Regulon*
  • Signal Transduction
  • Time Factors
  • Wnt Proteins / metabolism


  • Cadherins
  • Cell Adhesion Molecules, Neuronal
  • Chromatin
  • Cntn2 protein, mouse
  • Contactin 2
  • Efnb1 protein, mouse
  • Ephrin-B1
  • NFI Transcription Factors
  • Nfia protein, mouse
  • Nfib protein, mouse
  • Wnt Proteins
  • Wnt7a protein, mouse