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J. Biol. Chem., Vol. 279, Issue 51, 53491-53497, December 17, 2004

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A Role for Nuclear Factor I in the Intrinsic Control of Cerebellar Granule Neuron Gene Expression^*

Wei Wang, Rachel E. Stock, Richard M. Gronostajski, Yong Wee Wong¶, Melitta Schachner¶, and Daniel L. Kilpatrick||

From the University of Massachusetts Medical School, Department of Molecular and Cellular Physiology, Worcester, Massachusetts 01655, the ^¶Zentrum fur Molekulare Neurobiologie, Universitat Hamburg, Martinistrasse 52, 20246 Hamburg, Germany, and the Department of Biochemistry, State University of New York, Buffalo, New York 14214

Nervous system formation requires the elaboration of a complex series of differentiation events in both a spatially and maturation-regulated manner. A fundamental question is how neuronal subtype specification and developmental gene expression are controlled within maturing neurons. The 6 subunit of the -aminobutyric acid type A (GABA_A) receptor (GABRA6) is preferentially expressed in cerebellar granule neurons and is part of an intrinsic program directing their differentiation. We have employed a lentiviral approach to examine the transcriptional mechanisms controlling neuronal subtype-selective expression of this gene. These studies demonstrated that nuclear factor I (NFI) proteins are required for both transgenic GABRA6 promoter activity as well as endogenous expression of this gene in cerebellar granule neurons. Chromatin immunoprecipitation also showed that NFI proteins are bound to the GABRA6 promoter in these cells in vivo. Furthermore, analyses of gene knockout mice revealed that Nfia is specifically required for normal expression of the GABRA6 gene in cerebellar granule neurons. NFI expression and DNA binding activity are highly enriched in granule neurons, implicating this transcription factor family in the neuronal subtype-selective expression of the GABRA6 gene. These studies define a new role for NFI proteins as neuronal subtype-enriched transcriptional regulators that participate in an intrinsic transcriptional program directing the differentiation of cerebellar granule neurons.

Received for publication, September 9, 2004 , and in revised form, October 1, 2004.

^* This work was supported by Public Health Service Grants RO1CA79999 (to D. L. K.) and RO1DK58401 (to R. M. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article(available at http://www.jbc.org) contains Supplemental Table S1.

^|| To whom correspondence should be addressed: University of Massachusetts Medical School, BSB S4-139, 55 Lake Ave N., Worcester, MA 01655. Tel.: 508-856-6274; Fax: 508-856-5997; E-mail: daniel.kilpatrick{at}umassmed.edu.

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