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J. Biol. Chem., Vol. 280, Issue 16, 16484-16498, April 22, 2005

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Differences in Gene Expression between Wild Type and Hoxa1 Knockout Embryonic Stem Cells after Retinoic Acid Treatment or Leukemia Inhibitory Factor (LIF) Removal^*

Eduardo Martinez-Ceballos, Pierre Chambon, and Lorraine J. Gudas¶

From the Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10021 and the Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS/INSERM/Universite Louis Pasteur, College de France, BP 10142, 67404 Illkirch Cedex, France

Homeobox (Hox) genes encode a family of transcription factors that regulate embryonic patterning and organogenesis. In embryos, alterations of the normal pattern of Hox gene expression result in homeotic transformations and malformations. Disruption of the Hoxa1 gene, the most 3' member of the Hoxa cluster and a retinoic acid (RA) direct target gene, results in abnormal ossification of the skull, hindbrain, and inner ear deficiencies, and neonatal death. We have generated Hoxa1^-/- embryonic stem (ES) cells (named Hoxa1-15) from Hoxa1^-/- mutant blastocysts to study the Hoxa1 signaling pathway. We have characterized in detail these Hoxa1^-/- ES cells by performing microarray analyses, and by this technique we have identified a number of putative Hoxa-1 target genes, including genes involved in bone development (e.g. Col1a1, Postn/Osf2, and the bone sialoprotein gene or BSP), genes that are expressed in the developing brain (e.g. Nnat, Wnt3a, BDNF, RhoB, and Gbx2), and genes involved in various cellular processes (e.g. M-RAS, Sox17, Cdkn2b, LamA1, Col4a1, Foxa2, Foxq1, Klf5, and Igf2). Cell proliferation assays and Northern blot analyses of a number of ES cell markers (e.g. Rex1, Oct3/4, Fgf4, and Bmp4) suggest that the Hoxa1 protein plays a role in the inhibition of cell proliferation by RA in ES cells. Additionally, Hoxa1^-/- ES cells express high levels of various endodermal markers, including Gata4 and Dab2, and express much less Fgf5 after leukemia inhibitory factor (LIF) withdrawal. Finally, we propose a model in which the Hoxa1 protein mediates repression of endodermal differentiation while promoting expression of ectodermal and mesodermal characteristics.

Received for publication, December 22, 2004 , and in revised form, February 15, 2005.

^* This work was supported by National Institutes of Health Grants R01CA43796 (to L. J. G.) and UR 2U19HDO35466. 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.

^¶ To whom correspondence should be addressed: Dept. of Pharmacology, Weill Medical College of Cornell University, 1300 York Ave., Rm. E-409, New York, NY 10021. Tel.: 212-746-6250; Fax: 212-746-8858; E-mail: ljgudas{at}med.cornell.edu.

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				E. R. Lee, F. E. Murdoch, and M. K. Fritsch High Histone Acetylation and Decreased Polycomb Repressive Complex 2 Member Levels Regulate Gene Specific Transcriptional Changes During Early Embryonic Stem Cell Differentiation Induced by Retinoic Acid Stem Cells, September 1, 2007; 25(9): 2191 - 2199. [Abstract] [Full Text] [PDF]