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The Journal of Neuroscience, June 6, 2007, 27(23):6115-6127; doi:10.1523/JNEUROSCI.0180-07.2007

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Development/Plasticity/Repair
Nuclear Factor I Coordinates Multiple Phases of Cerebellar Granule Cell Development via Regulation of Cell Adhesion Molecules

Wei Wang,¹ Debra Mullikin-Kilpatrick,¹ James E. Crandall,^1,2 Richard M. Gronostajski,³ E. David Litwack,⁴ and Daniel L. Kilpatrick¹

¹Department of Cellular and Molecular Physiology and Program in Neuroscience, University of Massachusetts Medical School, Worcester, Massachusetts 01655, ²E. K. Shriver Center/University of Massachusetts Medical School, Waltham, Massachusetts 02452, ³Department of Biochemistry and Program in Neuroscience, State University of New York at Buffalo, Buffalo, New York 14214-3000, and ⁴Department of Anatomy/Neurobiology and Program in Neuroscience, University of Maryland, Baltimore, School of Medicine, Baltimore, Maryland 21201

Correspondence should be addressed to Daniel L. Kilpatrick, Physiology Department, University of Massachusetts Medical School, BSB S4-139, 55 Lake Avenue North, Worcester, MA 01655. Email: daniel.kilpatrick{at}umassmed.edu

A central question is how various stages of neuronal development are integrated as a differentiation program. Here we show that the nuclear factor I (NFI) family of transcriptional regulators is expressed and functions throughout the postmitotic development of cerebellar granule neurons (CGNs). Expression of an NFI dominant repressor in CGN cultures blocked axon outgrowth and dendrite formation and decreased CGN migration. Inhibition of NFI transactivation also disrupted extension and fasciculation of parallel fibers as well as CGN migration to the internal granule cell layer in cerebellar slices. In postnatal day 17 Nfia-deficient mice, parallel fibers were greatly diminished and disoriented, CGN dendrite formation was dramatically impaired, and migration from the external germinal layer (EGL) was retarded. Axonal marker expression also was disrupted within the EGL of embryonic day 18 Nfib-null mice. NFI regulation of axon extension was observed under conditions of homotypic cell contact, implicating cell surface proteins as downstream mediators of its actions in CGNs. Consistent with this, the cell adhesion molecules ephrin B1 and N-cadherin were identified as NFI gene targets in CGNs using inhibitor and Nfi mutant analysis as well as chromatin immunoprecipitation. Functional inhibition of ephrin B1 or N-cadherin interfered with CGN axon extension and guidance, migration, and dendritogenesis in cell culture as well as in situ. These studies define NFI as a key regulator of postmitotic CGN development, in particular of axon formation, dendritogenesis, and migratory behavior. Furthermore, they reveal how a single transcription factor family can control and integrate multiple aspects of neuronal differentiation through the regulation of cell adhesion molecules.

Key words: transcription; neuron; differentiation; axon; migration; dendrite

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Received Aug. 11, 2006; revised March 28, 2007; accepted April 23, 2007.

Correspondence should be addressed to Daniel L. Kilpatrick, Physiology Department, University of Massachusetts Medical School, BSB S4-139, 55 Lake Avenue North, Worcester, MA 01655. Email: daniel.kilpatrick{at}umassmed.edu

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