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J. Biol. Chem., Vol. 281, Issue 39, 29245-29255, September 29, 2006

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Evidence That the Satin Hair Mutant Gene Foxq1 Is among Multiple and Functionally Diverse Regulatory Targets for Hoxc13 during Hair Follicle Differentiation^*

Christopher S. Potter¹, Ron L. Peterson¹, Jeremy L. Barth^¶1, Nathanael D. Pruett¹, Donna F. Jacobs, Michael J. Kern^¶, W. Scott Argraves^¶, John P. Sundberg^||, and Alexander Awgulewitsch²

From the Departments of Medicine and ^¶Cell Biology, Medical University of South Carolina, Charleston, South Carolina 29425, Division of Integrative Expression Profiling, Novartis Institutes of Biomedical Research, Cambridge, Massachusetts 02139, and ^||the Jackson Laboratory, Bar Harbor, Maine 04609

It is increasingly evident that the molecular mechanisms underlying hair follicle differentiation and cycling recapitulate principles of embryonic patterning and organ regeneration. Here we used Hoxc13-overexpressing transgenic mice (also known as GC13 mice), known to develop severe hair growth defects and alopecia, as a tool for defining pathways of hair follicle differentiation. Gene array analysis performed with RNA from postnatal skin revealed differential expression of distinct subsets of genes specific for cells of the three major hair shaft compartments (cuticle, cortex, and medulla) and their precursors. This finding correlates well with the structural defects observed in each of these compartments and implicates Hoxc13 in diverse pathways of hair follicle differentiation. The group of medulla-specific genes was particularly intriguing because this included the developmentally regulated transcription factor-encoding gene Foxq1 that is altered in the medulladefective satin mouse hair mutant. We provide evidence that Foxq1 is a downstream target for Hoxc13 based on DNA binding studies as well as co-transfection and chromatin immunoprecipitation assays. Expression of additional medulla-specific genes down-regulated upon overexpression of Hoxc13 requires functional Foxq1 as their expression is ablated in hair follicles of satin mice. Combined, these results demonstrate that Hoxc13 and Foxq1 control medulla differentiation through a common regulatory pathway. The apparent regulatory interactions between members of the mammalian Hox and Fox gene families shown here may establish a paradigm for "cross-talk" between these two conserved regulatory gene families in different developmental contexts including embryonic patterning as well as organ development and renewal.

Received for publication, April 17, 2006 , and in revised form, July 5, 2006.

^* This work was supported in part by National Institutes of Health Grants AR47204-04 and RR00173 (to A. A. and J. P. S.) and in part by the Medical University of South Carolina Institutional Research Funds of 2004-2005. 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 a supplemental list.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Medicine, Medical University of South Carolina, 96 Jonathan Lucas St., Suite 912 CSB, Charleston, SC 29425. Tel.: 843-792-8946; Fax: 843-792-7121; E-mail: awgulewa{at}musc.edu.

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