UMMS Affiliation

Department of Cellular and Molecular Physiology and Program in Neuroscience; K. Shriver Center

Date

6-8-2007

Document Type

Article

Subjects

Animals; Cell Adhesion Molecules; Cell Movement; Cells, Cultured; Cerebellum; Drosophila; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; NFI Transcription Factors; Rats

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

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.

Rights and Permissions

Citation: J Neurosci. 2007 Jun 6;27(23):6115-27. Link to article on publisher's site

DOI of Published Version

10.1523/JNEUROSCI.0180-07.2007

Related Resources

Link to Article in PubMed

Journal Title

The Journal of neuroscience : the official journal of the Society for Neuroscience

PubMed ID

17553984

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